Dosage forms for oral administration and methods of treatment using the same

ABSTRACT

The invention relates to dosage forms that provide prolonged therapy. In particular, the invention relates to dosage forms including various pluralities of drug-containing resin particles. The invention also relates to methods of making these dosage forms and methods of treating using these dosage forms.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of International ApplicationNo. PCT/US2012/044698, filed Jun. 28, 2012, which claims priority toU.S. Provisional Application No. 61/502,189, filed Jun. 28, 2011, andU.S. Provisional Application No. 61/528,554, filed Aug. 29, 2011, thedisclosures of each of which are hereby incorporated by reference intheir entireties.

BACKGROUND OF THE INVENTION

(a) Field of the Invention

The invention relates to Attention Deficit Hyperactivity Disorder (ADHD)effective agent dosage forms that both facilitate oral ingestion andprovide an effective treatment over a prolonged period of time. Inparticular, the invention provides for pharmaceutical compositionshaving a first and second plurality of drug-resin particles, where thefirst plurality of drug-resin particles does not have a delayed releasecoating and the second plurality of drug-resin particles does have adelayed release coating, where the drug is an ADHD effective agent andthe composition achieves an escalating in vivo plasma concentration ofthe ADHD effective agent.

(b) Description of the Related Art

Many drug therapies use immediate-release oral dosage forms administeredat spaced intervals to provide and maintain a desired therapeutic effectover a prolonged therapy period. For example, drugs used in treatingAttention Deficit Disorder (ADD) and ADHD such as ADDERALL® and RITALIN®are administered two or three times a day.

For various reasons, subjects often experience difficulty complying withthis administration schedule. In particular, because ADD and ADHD arecommonly diagnosed in children, the dosage regimen generally requiresthat at least one dose is administered during the school day. Childrenare typically not permitted to self-administer the drug at school. Assuch, authorized school personnel generally take on the responsibilityfor administering the drug to children during the school day. However,this approach raises issues of medical privacy and potentialstigmatizing of the child by peers. In addition, the compliance issuebecomes further complicated as transportation, storage and supply of thedrug typically must be documented and/or monitored, and the schedules ofthe different parties involved, i.e., the child, the educators and theauthorized school personnel, must be coordinated and accommodated. Theunfortunate result is that doses may be given late or missed altogetherresulting in decreased efficacy of the therapy.

To avoid administering multiple doses during the day, once-a-daysustained and extended release medications have been developed. Forexample, ADDERALL XR®, a mixed amphetamine salts medication, isadministered once-a-day for the treatment of ADD and ADHD. To achieveextended release, ADDERALL XR requires a mixture of four amphetaminesalts: dextroamphetamine sulfate, dextroamphetamine saccharate,amphetamine aspartate, and amphetamine sulfate. U.S. Pat. Nos. 6,322,819and 6,605,300, which disclose ADDERALL XR, are hereby incorporated byreference in their entirety. U.S. Pat. No. 6,913,768, which is herebyincorporated by reference, also discloses a four amphetamine saltcomposition.

METADATE CD® is another once-a-day ADHD treatment. This formulationcomprises methylphenidate hydrochloride and achieves an extended-releaseprofile through its make up of 30% immediate release beads and 70%extended release beads.

Prior art ADHD compositions such as ADDERALL XR and METADATE CD are onlyavailable in solid dosage forms. Many people, especially children, havedifficulty swallowing standard solid dosage forms. Accordingly, there isa need in the art to develop easily ingested, once-daily oralcompositions that provide effective, prolonged treatment.

U.S. Pat. No. 2,990,332 to Keating discloses adsorbing amphetamines ontoa sulphonic acid cation exchange resin from which the drug is slowly anduniformly released by gastric and intestinal juices. In particular, thispatent discloses a homogeneous pharmaceutical drug compound which willimmediately release its drug continuously over a long period of timewithout the necessity of complicated and expensive enteric coatingprocedures. The amphetamine-resin complex of this patent is such thatnot more than approximately 50% of the amphetamine is released in onehour by elution with simulated gastric juice and at least approximately10% in three hours by such elution.

Hinsvark, et al. journal of Phamacokinetics and Biophaaceutics,1(4):319-328, 1973) reports the comparison of oral bioavailability andpharmacokinetics of between a resin-bound form of amphetamine and thesoluble hydrochloride salt. The efficiency of absorption was the samefor resinate as for soluble salt, but the speed of absorption was aboutthree times slower for the resinate and blood levels after the resinatereached a lower, later and flatter peak. Without any coating, theresin-bound amphetamine produced more sustained blood levels.

Although, as described by Keating and Hinsvark, amphetamine adsorbed onion exchange resin was released more slowly into gastric and/orintestinal juices than soluble salts, the pharmacokinetic profile is notcomparable to ADDERALL XR or METADATE CD. As such, there is still a needfor a once-a-day formulation that is easily ingested.

SUMMARY OF VARIOUS EMBODIMENTS OF THE INVENTION

The invention provides pharmaceutical compositions comprising drug-resinparticles comprising at least one ADHD effective agent (e.g.,amphetamine, methylphenidate), methods of making such compositions, andmethods of treatment using these compositions. In particular, theinvention provides for easily ingested, once-daily oral compositionsthat provide effective, prolonged treatment.

The invention provides various advantage over prior art compositions andmethods. For example, the invention provides for liquid drugsuspensions, chewable compositions, and orally disintegratingcompositions—compositions favored by individuals who have difficultyswallowing conventional solid dosage forms (e.g., children or dysphagicindividuals). Moreover, the compositions comprise ion-exchange resinsand thus have enhanced taste masking properties as compared totraditional drug formulations. The use of multiple coated resin beadsfor the controlled release portions of the compositions reduces the riskof dose dumping when the composition is chewed or crushed, because thereis no single point where failure of the controlled release mechanism canoccur.

In some embodiments, the compositions of the invention are advantageousas compared to currently available amphetamine compositions. Forexample, the compositions minimize the amount of sulfates, which reducesthe likelihood of formation alkyl sulfonates—toxic compounds that theFDA recommends limiting or excluding from drug formulations. Moreover,unlike ADDERALL XR, various compositions of the invention do not requirefour amphetamine salts. As such, the compositions streamline the supplychain by reducing the number of distinct components required, i.e.,simplifies processing and handling.

Also, in the presence of ethanol, the compositions have an improvedexposure level of amphetamines and methylphenidate compared to ADDERALLXR and METADATE CD, respectively, i.e., the invention reduces dosedumping when the composition and ethanol are ingested by a subject. Forexample, the inventors have shown that in the presence of varyingconcentrations of alcohol (e.g., 4%, 20%, and 40% ethanol) did notsignificantly alter the rate and extent of absorption of acontrolled-release ODT amphetamine composition described herein.

Also in the presence of food, the liquid suspension amphetaminecompositions have an increased exposure of amphetamines compared to fedADDERALL XR during the first four hours or up to the T_(max), i.e.,these compositions have less food effect than ADDERALL XR.

In particular, the invention relates to pharmaceutical compositionscomprising a plurality of drug-resin particles, wherein the drug in saiddrug-resin particles comprises at least one ADHD effective agent. Forexample, in one embodiment, the pharmaceutical composition comprises (a)at least one pharmaceutically active ADHD effective agent drug-resincomplex providing for immediate release; and (b) at least onepharmaceutically active ADHD effective agent drug-resin complex coveredwith a delayed release coating, wherein said component (a) provides foran immediate release of ADHD effective agent from the drug resin complexto provide a first blood level of ADHD effective agent and component (b)provides a delayed release of ADHD effective agent from the drug-resincomplex that increases the blood level of ADHD effective agent to asecond level.

In one embodiment, the ADHD effective agent is at least one amphetaminesuch as a mixture of amphetamine and dextroamphetamine (e.g., a mixtureof 75% dextroamphetamine and 25% levoamphetamine). In one embodiment,the compositions are substantially free of dextroamphetamine saccharateand/or amphetamine asparate. Alternatively, where the compositionsconsist essentially of amphetamine salts, anions of those salts arepolymeric. In another alternative, the compositions or the drug-resinparticles are substantially free of soluble anions. In anotherembodiment, the ADHD effective agent is methylphenidate.

In preferred embodiments, the compositions comprise a first plurality ofdrug-resin particles that are not coated with a delayed release coating,and a second plurality of drug-resin particles that are coated with adelayed release coating. The delayed release may comprise atriggered-release coating (e.g., where a pH change triggers thetriggered-release coating such as EUDRAGIT® L100). The particles coveredby a triggered-release coating may further comprise an extended releasecoating such as a diffusion barrier coating (e.g., a water insoluble,water permeable membrane such as ethylcellulose).

The compositions may comprise various amounts of the first and secondplurality of drug-resin particles. For example, in one embodiment, thecompositions comprise 20%-50% of the first plurality of drug-resinparticles and 50-80% of the second plurality of drug-resin particles. Inparticular, the compositions may comprise 40%-50%, or about 45%, of thefirst plurality of drug-resin particles and 50%-60% or about 55% of thesecond plurality of drug-resin particles. In other particularembodiments, the compositions may comprise 20%-30%, or about 25%, of thefirst plurality of drug-resin particles and 70%-80% or about 75% of thesecond plurality of drug-resin particles.

In some embodiments, the resin particles are strong acidic cationexchange resins such as polistirex, polacrilex, or polacrilin. In otherembodiments, the resin particles are AMBERLITE® IRP64, IRP69, or IRP88resins, or DUOLITE™ AP143 resins. The compositions may be liquidsuspensions, chewable compositions, or an orally disintegrating tabletcompositions.

The invention provides for compositions having unique in vitrodissolution profiles. In particular, the rate of appearance of the drugin a dissolution medium increases after a period of decrease in the rateof appearance of the drug in the dissolution medium. The period ofdecrease in the rate of appearance of the drug may occur within 0.5, 1,1.5, 2, or 2.25 hours after the composition is introduced into thedissolution medium. In some embodiments, 30-60% of the drug may bereleased before the rate of appearance of the drug in a dissolutionmedium increases. Typically, release of 80% or more of the drug isachieved only after the rate of appearance of the drug in thedissolution medium has decreased and then increased. In particular, 80%or more of the drug is released during the dissolution assay within thefirst half (i.e., within 12 hours) of the dosing interval (i.e., 24 hourdosing interval).

In other embodiments, 40-45% of the drug is released within the first 45minutes after the drug-resin particles are introduced into a dissolutionassay, followed by a period of substantially no drug release from 45minutes to 2 hours, and concluding with period of from 2 to 8 hoursduring which substantially all of the remaining drug is released. Inanother embodiment, 40-45% of the drug is released within the first 45minutes after the drug-resin particles are introduced into a dissolutionassay, 45-50% of the drug is released within 2 hours, and 50-100% of thedrug is released by 8 hours. In another embodiment, 30-33% of the drugis released the first 30 minutes after the drug-resin particles areintroduced into a dissolution assay, 34-42% of the drug is releasedwithin 2 hours, 40-80% of the drug is released within 4 hours and80-100% of the drug is released within 24 hours. In any of theseembodiments, the conditions of the dissolution assay are an initialdissolution medium of 0.1 N HCL, and after 2 hours, the medium isadjusted to a pH of ˜6.8; and dissolution testing is performed using aUSP Apparatus 2.

The invention also provides for compositions having unique in vivo serumprofiles. In some embodiments, the composition has an in vivo serumprofile with a first and second peak (e.g., where the second peak is theC_(max)). For example, the composition may have an in vivo serum profilewith a first peak between 1 and 3 hours after ingestion of thecomposition, and with a second peak between 4 and 7 hours afteringestion of the composition. In a particular mode, the composition mayhave an in vivo serum profile with a first peak between 1 and 2.5 hoursafter ingestion of the composition, and with a second peak between 4 and6 hours after ingestion of the composition. Alternatively, thecomposition may have an in vivo serum profile that reaches atherapeutically effective level fairly rapidly (1-3 hours) and themcontinues to increase more slowly up to a maximum serum level between 4hours and 7 hours after ingestion.

In one aspect, the compositions have in vivo serum profilesbioequivalent to the profiles of compositions described in the Examplesand shown in the Figures. In particular aspect, the in vivo serumprofile of the composition is bioequivalent to the in vivo serum profileof ADDERALL XR (e.g., under fasted conditions). In other embodiments,the compositions have one or more partial AUCs (e.g., AUC₀₋₄, AUC₀₋₅,AUC₄₋₁₂, AUC₅₋₁₂, AUC_(5-t) (AUC_(5-last))¹, AUC₀₋₂₄, and/or AUC_(0-∞))which meet the bioequivalence conditions of the compositions describedin the Examples (e.g., ADDERALL XR) and shown in the Figures. In anotherembodiment, the composition, in the presence of ethanol, provides thatthe recipient of the composition is exposed to a reduced amount ofamphetamines compared to ADDERALL XR. ¹(AUC_(5-last))=AUC_(5-t)=the areaunder the plasma concentrate time curve for the time between 5 hoursafter ingestion to the last data point collected.

The invention also provides for methods of treating various conditionssuch as Attention-Deficit Disorder or ADHD, fatigue, obesity orimparting alertness, by administering an effective amount of thecompositions described herein. In one embodiment, the amount of drugdelivered to the subject is between about 2 mg/24 hours to about 60mg/24 hours. In another embodiment, the amount of drug delivered to thesubject is about 5 mg/24 hours to about 30 mg/24 hours. In particularembodiments, the effective amount is 0.5 mg/kg/day to 1.5 mg/kg/day,0.25 mg/kg/day to 0.5 mg/kg/day, or 0.28/kg/day to 0.4 mg/kg/day. Thecomposition may be administered once-a-day as a single or multiple unitdose. This invention is preferred for a subject suffering fromdysphagia.

The invention also relates to methods of reducing the effects of anelevated exposure of a subject to ADHD effective agents (e.g.,amphetamines). For example, when the compositions are administeredsubstantially contemporaneously with ethanol, such that the subject isexposed to a reduced amount of amphetamines compared to administeringADDERALL XR to a subject substantially contemporaneously with ethanol.

The invention also provides for various methods of making thecompositions. In one embodiment, the method involves (a) loading aplurality of resin particles with at least one ADHD effective agent(e.g., at least one amphetamine, methylphenidate) to form drug-resinparticles; (b) coating a subset of the drug-resin particles with atriggered-release coating to form coated drug-resin particles; and (c)combining uncoated drug-resin particles with the subset of coateddrug-resin particles in a pharmaceutical composition. In anotherembodiment, the method involves (a) loading a plurality of resinparticles with an ADHD effective agent (e.g., methylphenidate) to formdrug-resin particles; (b) coating drug-resin particles with an extendedrelease coating (e.g., ethyl cellulose) to form extended release coateddrug-resin particles; (c) further coating the extended release coateddrug-resin particles with a delayed release coating (e.g.,triggered-release coating) to form extended release/delayed releasecoated drug-resin particles; and (d) combining loaded, but uncoateddrug-resin particles with the extended release/delayed release coateddrug-resin particles in a pharmaceutical composition.

In another embodiment, the composition, wherein, for in vivopharmacokinetic parameters of the composition, one or more in vivopharmacokinetic parameters selected from the group consisting ofC_(max), AUC₀₋₅, AUC₅₋₁₂, AUC₅₋₂₄, AUC_(5-t) (AUC_(5-last)), AUC₀₋₁₂,AUC₀₋₂₄, AUC_(0-t), and AUC_(0-∞) have a 90% confidence interval withupper and lower bounds within a range from 90%-115% of the value of thesame parameter(s) for a bioequivalent reference composition (e.g.,ADDERALL XR).

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts an exemplary process for loading amphetamines onto resinparticles.

FIG. 2 shows the dissolution profile of the composition described inExample 4.

FIG. 3 shows the dissolution profile of the composition described inExample 5.

FIG. 4 shows the dissolution profile of the composition described inExample 6.

FIG. 5 shows the dissolution profile of the composition described inExample 7.

FIG. 6 shows the dissolution profile of the composition described inExample 8.

FIG. 7 shows the dissolution profile of the composition described inExample 9.

FIG. 8 shows the results of a pH study on different coated resinsdescribed in Example 10.

FIG. 9 shows the plasma concentrations of amphetamine released from twodifferent amphetamine formulations compared to ADDERALL XR (i.e., thereference formulation) in the pig study described in Example 12.

FIGS. 10A and 10B shows the plasma concentrations of exemplaryamphetamine formulations compared to ADDERALL XR (i.e., the referenceformulation) with alcohol and without alcohol as described in Example13A. FIG. 10A shows the results of d-amphetamine.

FIG. 10B shows the results of l-amphetamine.

FIG. 11 shows in vitro release profiles of ADDERALL XR (i.e., thereference formulation) with the addition of 0%, 20%, and 40% alcohol asdescribed in Example 13B.

FIG. 12 shows the in vitro release profiles of the drug sample similarto that in Example 6 with the addition of 0%, 20%, and 40% alcohol asdescribed in Example 13B.

FIG. 13 shows the amount of drug released over a range of pHs for threedifferent lots of the delayed release product described in Example 6.

FIGS. 14A and 14B show the mean d-amphetamine concentration-timeprofiles after administration of Test Formulation #1 (Treatment A), TestFormulation #2 (Treatment B), and Reference Product (Treatment C), asdescribed in Example 15.

FIGS. 15A and 15B show the mean l-amphetamine concentration-timeprofiles after administration of test formulation #1 (Treatment A), testformulation #2 (Treatment B), and reference product (Treatment C), asdescribed in Example 15.

FIG. 16 shows the mean d-amphetamine concentration-time profiles afteradministration of the ODT formulation and Reference Product (ADDERALLXR), as described in Example 16.

FIG. 17 shows the mean l-amphetamine concentration-time profiles afteradministration of the ODT formulation and Reference Product (ADDERALLXR), as described in Example 16.

FIG. 18 shows the mean d-amphetamine concentration-time profiles afteradministration of the suspension formulation and Reference Product(ADDERALL XR), as described in Example 16.

FIG. 19 shows the mean l-amphetamine concentration-time profiles afteradministration of the suspension formulation and Reference Product(ADDERALL XR), as described in Example 16.

FIGS. 20A and 20B show the mean d-methylphenidate concentration-timeprofiles after administration of Test Formulation #1 (Treatment A), TestFormulation #2 (Treatment B), and Reference Product (Treatment C), asdescribed in Example 18.

FIGS. 21A and 21B show the mean 1-methylphenidate concentration-timeprofiles after administration of Test Formulation #1 (Treatment A), TestFormulation #2 (Treatment B), and Reference Product (Treatment C), asdescribed in Example 18.

FIGS. 22A and 22B show the mean total methylphenidate (d+l)concentration-time profiles after administration of Test Formulation #1(Treatment A), Test Formulation #2 (Treatment B), and Reference Product(Treatment C), as described in Example 18.

FIG. 23 shows the mean d-amphetamine and l-amphetamine plasmaconcentrations following administration of ADDERALL XR 20 mg (8 am) andADDERALL (immediate-release) 10 mg twice daily (8 am and noon) in thefed state as reported in the prior art.

FIG. 24 shows the mean plasma concentrations following administration ofimmediate release methylphenidate and METADATE CD formulations asreported in the prior art.

FIGS. 25A-25C show in vitro release profiles of METADATE CD (i.e., thereference drug) with the addition of 0%, 5%, 10%, 20%, and 40% alcohol(FIG. 25A), the in vitro release profiles of a formulation similar tothose formulations described in Example 17 with the addition of 0%, 5%,10%, 20%, and 40% alcohol (FIG. 25B), and the in vitro release profilesof METADATE CD and a formulation similar to those described in Example17 with the addition of 0%, 5%, 10%, 20%, and 40% alcohol (FIG. 25C).

FIG. 26 shows the dissolution profile of compositions A and B describedin Example 17.

FIGS. 27A and 27B show the mean methylphenidate (d+l) concentration-timeprofiles after administration of Formulation #102-Fasted (Treatment A)and Formulation #102-Fed (Treatment B), as described in Example 20.

FIGS. 28A and 28B show the mean d-methylphenidate concentration-timeprofiles after administration of Formulation #102-Fasted (Treatment A)and Formulation #102-Fed (Treatment B), as described in Example 20.

FIGS. 29A and 29B show the mean l-methylphenidate concentration-timeprofiles after administration of Formulation #102-Fasted (Treatment A)and Formulation #102-Fed (Treatment B), as described in Example 20.

FIGS. 30A and 30B show the mean d-amphetamine concentration-timeprofiles after administration of test formulation-fed (Treatment A) andtest formulation-fasted (Treatment B), as described in Example 21.

FIGS. 31A and 31B show the mean l-amphetamine concentration-timeprofiles after administration of test formulation-fed (Treatment A) andtest formulation-fasted (Treatment B), as described in Example 21.

FIGS. 32A and 32B show the mean d-amphetamine concentration-timeprofiles after administration of controlled release ODT with DeionizedWater (0% Ethanol Solution) (Treatment A), 4% ethanol (Treatment B), 20%ethanol (Treatment C) and 40% ethanol (Treatment D) on linear (upperpanel) and semi-logarithmic (lower panel) scales, as described inExample 22.

FIGS. 33A and 33B shows the mean l-amphetamine concentration-timeprofiles after administration of controlled release ODT with DeionizedWater (0% Ethanol Solution) (Treatment A), 4% ethanol (Treatment B), 20%ethanol (Treatment C) and 40% ethanol (Treatment D) on linear (upperpanel) and semi-logarithmic (lower panel) scales, as described inExample 22.

FIGS. 34A and 34B mean d-amphetamine concentration-time profiles afteradministration of amphetamine-containing ODT for Group 1 (Ages 6-7),Group 2 (Ages 8-9), and Group 3 (Ages 10-12), as described in Example23.

FIGS. 35A and 35B mean d-amphetamine concentration-time profiles afteradministration of amphetamine-containing ODT for Group 1 (Ages 6-7),Group 2 (Ages 8-9), and Group 3 (Ages 10-12), as described in Example23.

FIGS. 36A and 36B show the mean d-amphetamine concentration-timeprofiles after administration of Test Formulation #1 (Treatment A), TestFormulation #2 (Treatment B), Test Formulation #3 (Treatment C), and theReference Product (Treatment D), as described in Example 24.

FIGS. 37A and 37B show the mean l-amphetamine concentration-timeprofiles after administration of Test Formulation #1 (Treatment A), TestFormulation #2 (Treatment B), Test Formulation #3 (Treatment C), and theReference Product (Treatment D), as described in Example 24.

FIG. 38: Mean d-Amphetamine Concentration-Time Profiles afterAdministration of Suspension under Fasted Conditions (Treatment A),Suspension under Fed Conditions (Treatment B), and the Reference Productunder Fed Conditions (Treatment C).

FIG. 39: Mean 1-Amphetamine Concentration-Time Profiles afterAdministration of Suspension under Fasted Conditions (Treatment A),Suspension under Fed Conditions (Treatment B), and the Reference Productunder Fed Conditions (Treatment C)

DETAILED DESCRIPTION OF THE INVENTION

The invention provides for various dosage forms comprising drug-resinparticles that provide an effective treatment over a prolonged period oftime. The invention provides pharmaceutical compositions such as liquiddrug suspensions, chewable compositions, or orally disintegratingcompositions comprising at least one plurality of drug-resin particlescomprising a delayed-release coating. The invention also provides formethods of making pharmaceutical compositions and methods of treatmentusing these pharmaceutical compositions.

For example, the invention provides for such pharmaceutical compositionsin which (i) the rate of appearance of the drug (e.g., at least oneamphetamine) in a dissolution medium is increasing during a time periodfrom a first time point through to a second time point, wherein thefirst time point is at least one hour after the composition isintroduced into the dissolution medium; and/or (ii) the compositionachieves an ascending plasma concentration of the drug (e.g., at leastone amphetamine) after a therapeutically effective level is reached(e.g., one, two, three hours after ingestion of the composition).

The inventors have also observed that, when monitoring the release ofthe compositions of the invention and a reference listed ADHD effectiveagent (e.g., amphetamine, methylphenidate) in vivo, contemporaneousconsumption of alcohol and drug affected both the rate and amount ofADHD effective agent appearing in the subject's circulation.Consequently, alcohol consumption by a patient being treated for ADHDcan substantially increase the patient's level of exposure to ADHDeffective agent (e.g., amphetamine, methylphenidate). The compositionsof this invention help control the exposure, by reducing dose dumping.

DEFINITIONS

As used herein, a “drug-resin particle” is a drug-containingion-exchange resin particle in which there is an ionic bond between thedrug and the ion-exchange resin particle.

As used herein, an “ADHD effective agent” is any agent effective totreat ADHD or ADD in any patient population (e.g., children,adolescents, adults), wherein the agent includes stimulants such asamphetamine, lisdexamphetamine, methylphenidate, and their opticalisomers; non-stimulants such as atomoxetine, guanfacine, and clonidine;antidepressants such as bupropion; anti-hypertussives such as gaunfacineand clonidine, derivatives thereof, or any combination that comprises atleast one of these agents. As discussed herein, ADHD effective agentsmay also be used in the effective treatment of other conditions such asfatigue, obesity and for imparting alertness.

As used herein, “controlled release” means the time course of drugappearance in medium surrounding the composition is modified compared toan immediate release composition. Controlled release encompasses“delayed release” and “extended release” formulations.

As used herein, “delayed release” means that appearance of drug in themedium surrounding the composition occurs after a time lapse. An exampleof a delayed release coating is a triggered-release coating.

As used herein, a “triggered-release coating” is a coating that degradesas a result of a triggering event, where the triggering event is achange in the physiological environment of surrounding thetriggered-release coating. Triggering events include, but are notlimited to, a pH change which occurs upon transit from one stage toanother stage in a subject's GI tract, an enzyme secreted in aparticular region in a subject's GI tract, or enzymatic presence indigestion.

As used herein, “extended release” means that the rate of release isslower than the rate for an immediate release or delayed releasecomposition from the initial point of release.

As used herein, “immediate release” means the initial period duringwhich drug is released from the composition that does not involvedelayed or extended release but may include taste-masking.

As used herein, a “subject” means any animal, but is preferably amammal, such as, for example, a human.

As used herein, “dose dumping” means the premature and/or acceleratedrelease of a drug. Dose dumping could produce adverse effects ortoxicity due to exposure of the patient to higher levels of the drug.

As used herein, “substantially free of dextroamphetamine saccharateand/or amphetamine asparate” means little to no dextroamphetaminesaccharate and/or amphetamine asparate is present. Thus, while traceamounts of dextroamphetamine saccharate and/or amphetamine asparate maybe included, therapeutically effective levels of dextroamphetaminesaccharate and/or amphetamine asparate are excluded.

As used herein, “substantially free of soluble anions” means little tono soluble anions may be included. Thus, while trace amounts of solubleanions may be included, these trace amounts will affect the release ofthe drug by no more than 5%, preferably no more than 2%. Particularly,the trace amounts will affect the release of the drug by no more than5%, preferably no more than 2%, during the first half hour afteringestion of the drug or after introduction of the drug to a dissolutionassay.

As used herein, “substantially contemporaneously with ethanol” meansingesting (or introducing) a substance containing ethanol (e.g., beer,wine, hard liquor) within 5, 10, 15, 30, 45, 60, 75, 90, or 120 minutesbefore or after ingesting (or introducing) a composition of theinvention.

As used herein, “substantially all,” in the context of drug release,means 90% or more.

As used herein, “substantially similar” parameters have values within−20%/+25% of each other.

Bioavailability

Measures of bioavailability well known in the art include the area underthe plasma concentration-time curve (AUC), the concentration maximum(C_(max)), and the time to C_(max) (T_(max)).

AUC is a measurement of the area under the plasma concentration-timecurve, and is representative of the amount of drug absorbed followingadministration of a single dose of a drug (see Remington: The Scienceand Practice of Pharmacy, (Alfonso R. Gennaro ed. 2000), page 999).

C_(max) is the maximum plasma concentration achieved after oral drugadministration (see Remington, page 999). An oral drug administrationresults in at least one C_(max), but may result in more than one “peakplasma concentration” or “plasma concentration peak” (for example,following the administration of a pulsed dose formulation).

T_(max) is the amount of time necessary to achieve the C_(max) afteroral drug administration, and is related to the rate of absorption of adrug (see Remington, page 999).

Bioequivalence is the absence of a significantly different rate andextent of absorption in the availability of the active ingredient whenadministered at the same dose under similar conditions. Bioequivalencecan be measured by pharmacokinetic parameters such as, for example, AUCand C_(max). According to the FDA, two products are bioequivalent if the90% confidence intervals of the relative mean AUC, C_(max), and T_(max)of the test formulation are within 80% to 125% (−20%/+25%) of thereference formulation drug when administered in the fasting state. In aparticular embodiment, bioequivalence may be established by comparing atest drug to a reference drug by comparing partial AUCs (e.g., overstatistically or clinically relevant time intervals). Thisbioequivalence measure based partial AUCs may be used alone or incombination with the bioequivalence measure discussed above.

As used herein, a dissolution profile is “statistically similar” toanother profile if the f2 similarity factor calculated for the twoprofiles is greater than or equal to 50. (See Moore and Flanner, Pharm.Tech. 20: 64-74, 1996).

Drug-Containing Resin Particles

The invention provides for various dosage forms comprisingdrug-containing ion-exchange resin particles. These particles generallycomprise at least one ADHD effective agent (e.g., at least oneamphetamine, methylphenidate) bound to particles of an ion-exchangeresin to provide a drug-resin complex. This complex may be coated with(i) a delayed release coating (e.g., triggered-release coating); (ii) anextended release coating (e.g., a water-permeable diffusion barriercoating that is insoluble in gastrointestinal fluids (and water) therebyproviding a controllable extended release of drug under conditionsencountered in the gastrointestinal tract); or (iii) both (i) and (ii).The drug-resins may also include a slow-dissolve polymer coating.Alternatively, the drug-resin particles are uncoated, i.e., omit adelayed release coating (e.g., triggered-release coating) and/or othercoating (e.g., water-permeable diffusion barrier coating).

Resins

Ion-exchange resins suitable for use in the preparations and methodsdescribed herein are water-insoluble and comprise an indigestibleorganic and/or inorganic matrix containing covalently bound functionalgroups that are ionic or capable of being ionized under the appropriateconditions of pH. The organic matrix may be synthetic (e.g., polymers orcopolymers of acrylic acid, methacrylic acid, sulfonated styrene,sulfonated divinylbenzene), or partially synthetic (e.g., modifiedcellulose and dextrans). The inorganic matrix preferably comprisessilica gel modified by the addition of ionic groups. Covalently boundionic groups may be strongly acidic (e.g., sulfonic acid, phosphoricacid), weakly acidic (e.g., carboxylic acid), strongly basic (e.g.,primary amine), weakly basic (e.g. quaternary ammonium), or acombination of acidic and basic groups. In general, the types ofion-exchangers suitable for use in ion-exchange chromatography and forsuch applications as deionization of water are suitable for use in thecontrolled release of drug preparations. Suitable ion exchange resinsare also sold under the trade names AMBERLITE and Dowex. Suchion-exchangers are described by H. F. Walton in “Principles of IonExchange” (pp. 312-343) and “Techniques and Applications of Ion-ExchangeChromatography” (pp. 344-361) in Chromatography. (E. Heftmann, editor),Van Nostrand Reinhold Company, New York (1975), incorporated herein byreference. Exemplary ion-exchange resins that can be used in the presentinvention have exchange capacities below about 6 milliequivalents(meq)/gram and preferably below about 5.5 meq/gram.

Typically, the size of the ion-exchange particles is from about 30microns to about 500 microns, preferably the particle size is within therange of about 40 micron to about 150 micron for liquid dosage forms,although particles up to about 1,000 micron can be used for solid dosageforms, e.g., tablets and capsules. Particle sizes substantially belowthe lower limit are difficult to handle in all steps of the processing.Commercially-available ion-exchange resins having an irregular shape andlarger diameters up to about 200 micron are gritty in liquid dosageforms. Moreover, it is believed that the increased distance that adisplacing ion must travel in its diffusion into these large particles,and the increased distance the displaced drug must travel in itsdiffusion out of these large particles, cause a measurable but notreadily controlled prolongation of release, even when the drug-resincomplexes are uncoated. Release of drug from uncoated drug-resincomplexes with particle sizes in the approximate range of 40 micron to150 micron is relatively rapid in the appropriate environment.Satisfactory control of the release from such complexes is achievedalmost exclusively by applying a diffusion barrier coating.

Both regularly and irregularly shaped particles may be used as resins.Regularly shaped particles are those particles that substantiallyconform to geometric shapes, such as spherical, elliptical, cylindricaland the like, which are exemplified by Dow XYS-40010.00 and DowXYS-40013.00 (The Dow Chemical Company). Irregularly shaped particlesare all particles not considered to be regularly shaped, such asparticles with amorphous shapes and particles with increased surfaceareas due to surface channels or distortions. Irregularly shapedion-exchange resins of this type are exemplified by AMBERLITE IRP-69(Rohm and Haas). Two of the preferred resins of this invention areAMBERLITE IRP-69 and Dow XYS-40010.00. Both are sulfonated polymerscomposed of polystyrene cross-linked with 8% of divinylbenzene, with anion-exchange capacity of about 4.5 to 5.5 meq/g of dry resin (Na⁺-form).Their essential difference is in physical form. AMBERLITE IRP-69consists of irregularly-shaped particles with a size range of 47 micronto 149 micron produced by milling the parent large-sized spheres ofAMBERLITE® IRP-120. The Dow XYS-40010.00 product consists of sphericalparticles with a size range of 45 micron to 150 micron. Another usefulexchange resin, Dow XYS-40013.00, is a polymer composed of polystyrenecross-linked with 8% of divinylbenzene and functionalized with aquaternary ammonium group; its exchange capacity is normally within therange of approximately 3 to 4 meq/g of dry resin.

The following U.S. patents and Publications describe resins suitable foruse in the preparations and methods described herein: U.S. Pat. Nos.4,221,778; 4,996,047; and 5,980,882; U.S. Publication Nos. 2003/0099711;2006/0193877; 2007/0059270; 2007/01400983; 2007/0148239; and2009/0011027. The disclosure of each of these patents and publicationsis incorporated by reference herein in their entireties.

Drugs

Drugs that are suitable for the invention may be acidic, basic oramphoteric. Basic drugs that can be used in the present inventioninclude amphetamine and methylphenidate. Drugs which may be used in theinvention include ADHD effective agents such as amphetamine,dextroamphetamine, levoamphetamine, lisdexamphetamine, methylphenidate,dexmethylphenidate, atomoxetine, guanfacine, clonidine, and bupropion.In preferred embodiments, the drug is a stimulant such as amphetamineand methylphenidate.

Drug-Resin Complexes

Binding of drug to resin can be accomplished using methods known in theart. Indeed, one of ordinary skill in the art can easily determine theappropriate method depending upon the drug. Typically four generalreactions are used for a basic drug, these are: (a) resin (Na⁺-form)plus drug (salt form); (b) resin (Na⁺-form) plus drug (as free base);(c) resin (H⁺-form) plus drug (salt form); and (d) resin (H⁺-form) plusdrug (as free base). All of these reactions except (d) have cationicby-products and these by-products, by competing with the cationic drugfor binding sites on the resin, reduce the amount of drug bound atequilibrium. For basic drugs, stoichiometric binding of drug to resin isaccomplished only through reaction (d).

Typically, the ion-exchange resin, in the form indicated by the chosenreaction, is placed in an aqueous solution of the chosen form of drugand agitated. The drug-resin complex thus formed is collected and washedwith deionized or purified water to ensure removal of any unbound drug.The complexes are then dried.

Uncoated drug-resin complexes rapidly release the drug in the subject,such as, for example, in the gastrointestinal tract. To delay therelease of drug from the drug-resin complex, the complex may be coatedas described below.

The amount of drug that can be loaded onto a resin will typically rangefrom about 1% to about 80%, preferably about 15% to about 60%, by weightof the loaded drug-resin particles. A skilled artisan with little or noexperimentation can readily determine the optimum loading for any drugresin complex. In a preferred embodiment, loadings of about 30% to about60% by weight of the drug-resin particles can be employed.

Those of skill in the art will appreciate that certain drugs will havean affinity for particular types of resins. The inventors havedetermined that the loading levels of amphetamine are suitable onstrongly acidic cation exchange resins such as AMBERLITE IRP-64 andAMBERLITE IRP-69 resins. Resins useful in the invention withmodification of the API are strong base anion exchange resins (e.g.,DUOLITE™ AP143) and weak acid cation exchange resins (e.g., AMBERLITEIRP-88).

Amphetamine resin complexes can be formed using any amphetamine salt,since the salt counter-ion is replaced by the ion exchange resin, andrelease of the drug is controlled by coating and ionic bonding, ratherthan differential solubility of the salts. In a preferred mode, resinparticles are loaded using a single salt of racemic amphetamine and asingle salt of dextroamphetamine.

The following U.S. patents and Publications describe preparations andmethods suitable for drug-resin complexes described herein: U.S. Pat.Nos. 4,221,778; 4,996,047; and 5,980,882; U.S. Publication Nos.2003/0099711; 2006/0193877; 2007/0059270; 2007/01400983; 2007/0148239;and 2009/0011027. The disclosure of each of these patents andpublications is incorporated by reference herein in their entireties.

Impregnation

Drug-resin particles can be impregnated with a humectant substantiallyas described in U.S. Pat. No. 4,221,778. The humectant can be added asan ingredient in the resin drug complexation step or, preferably, theparticles can be treated with the humectant after complexing. Thistreatment helps particles retain their geometry, and enables theeffective application of diffusion barrier coatings to such particles.One preferred humectant is polyethylene glycol, a hydrophilic agent.Other effective humectant agents include, for example, propylene glycol,lactose, methylcellulose, hydroxypropylmethylcellulose, sugar alcoholssuch as sorbitol, mannitol, polyvinylpyrrolidone, carboxypolymethylene,xanthan gum, propylene glycol, alginate and combinations of theseagents. The humectant may be added in an amount of up to about 50 partsper 100 parts by weight of the resin or 50 to 150 parts per 100 parts ofthe resin; such humectant levels have been found to be effective.Preferably, the humectant (solvating agent) is added in an amount ofabout 75 to about 100 parts per 100 parts of resin.

Coatings

Coating layers can provide immediate release, delayed release, pulsedrelease, or extended release of drug from the drug-resin particle.Immediate release of the drug from the immediate-release layer can beachieved by any of various methods known in the art. One example is theuse of a very thin layer or coating which by virtue of its thinness isquickly penetrated by gastric fluid allowing rapid leaching of the drug.Another example is by incorporating the drug in a mixture that includesa supporting binder or other inert material that dissolves readily ingastric fluid, releasing the drug as the material dissolves. A third isthe use of a supporting binder or other inert material that rapidlydisintegrates upon contact with gastric fluid, with both the materialand the drug quickly dispersing into the fluid as small particles.Examples of materials that rapidly disintegrate and disperse are lactoseand microcrystalline cellulose.

The following U.S. patents and Publications describe coating materialssuitable for use in the preparations and methods described herein: U.S.Pat. Nos. 4,221,778; 4,996,047; and 5,980,882; U.S. Publication Nos.2003/0099711; 2006/0193877; 2007/0059270; 2007/01400983; 2007/0148239;US 2007/0264323; and 2009/0011027. The disclosure of each of thesepatents and publications is incorporated by reference herein in theirentireties.

Diffusion Barrier Coating

Loaded particles may be coated with a diffusion barrier comprising awater-permeable, film-forming polymer. Any coating procedure whichprovides a contiguous coating on each particle of drug-resin complexwithout significant agglomeration of particles may be used. Coatings maybe applied with a fluid-bed coating apparatus having the Wursterconfiguration. Measurements of particle size distribution can be donebefore and after coating to show that agglomeration of particles isacceptable.

The polymer may be any of a large number of natural or syntheticfilm-formers used singly, or in admixture with each other, andoptionally in admixture with plasticizers, pigments and other substancesto alter the characteristics of the coating. In general, the diffusionbarrier coating should be insoluble or slowly soluble in water andpermeable to water. Additional examples of coating polymers aredescribed by R. C. Rowe in Materials Used in Pharmaceutical Formulation(A. T. Florence, editor), Blackwell Scientific Publications, Oxford,1-36 (1984), incorporated by reference herein.

Preferably, the diffusion barrier is ethyl cellulose, for example, anethyl cellulose having the content of ethoxyl group from 44 to 47.5%,preferably from 45 to 46.5%. In embodiments of the present invention,the inclusion of an effective amount of a plasticizer in the aqueousdispersion of hydrophobic polymer will further improve the physicalproperties of the film. For example, because ethylcellulose has arelatively high glass transition temperature and does not form flexiblefilms under normal coating conditions, it may be necessary to addplasticizer to the ethylcellulose before using the same as a coatingmaterial. Generally, the amount of plasticizer included in a coatingsolution is based on the concentration of the film-former, e.g., mostoften from about 1 to about 50 percent by weight of the film-former.Concentration of the plasticizer, however, can only be properlydetermined after routine experimentation with the particular coatingsolution and method of application.

Examples of suitable plasticizers for ethylcellulose include waterinsoluble plasticizers such a dibutyl sebacate, diethyl phthalate,triethyl citrate, tributyl citrate and triacetin, although it ispossible that other water-insoluble plasticizers (such as acetylatedmonoglycerides, phthalate esters, castor oil, etc.) may be used. Aplasticizer such as Durkex 500 vegetable oil may also be incorporated toimprove the film forming property. In one alternative, it is desirableto incorporate a water-soluble substance, such as methyl cellulose, toalter the permeability of the coating.

The diffusion barrier coating materials can be applied as an aqueoussuspension. One commercially available aqueous dispersion ofethylcellulose is Aquacoat® (FMC Corp., Philadelphia, Pa., U.S.A.).Aquacoat® is typically prepared by dissolving the ethylcellulose in awater-immiscible organic solvent and then emulsifying the same in waterin the presence of a surfactant and a stabilizer. After homogenizationto generate submicron droplets, the organic solvent is evaporated undervacuum to form a pseudolatex. The plasticizer is not incorporated in thepseudolatex during the manufacturing phase. Thus, prior to using thesame as a coating, it is preferable to intimately mix the Aquacoat® witha suitable plasticizer prior to use.

Another aqueous dispersion of ethylcellulose is commercially availableas Surelease® (Colorcon, Inc., West Point, Pa., U.S.A.). This product istypically prepared by incorporating plasticizer into the dispersionduring the manufacturing process. A hot melt of a polymer, plasticizer(e.g., dibutyl sebacate), and stabilizer (e.g., oleic acid) may beprepared as a homogeneous mixture, which is then diluted with analkaline solution to obtain an aqueous dispersion which can be applieddirectly onto substrates.

Another alternative coating material is a mixture of an insoluble,film-forming polymer and a water soluble pore former or polymer, i.e.,refers to a two-component system. One preferred water soluble polymer ismethyl cellulose, which may be used in a two-component system withethylcellulose.

Another alternative coating material is a mixture of two insoluble,film-forming polymers; for example polyvinyl acetate phthalate (PVAP)and ethylcellulose. Another alternative coating material ispolyvinylpyrrolidone (PVP), polyvinylalcohol, polyvinylacetate andmixtures thereof.

Typically, the water-permeable, film-forming polymer comprises fromabout 1% to about 60% by weight of the drug-resin complex, andpreferably from about 20% to about 50% by weight of the dry resin. Interms of coat thickness, preferably, the diffusion barrier coatthickness is at least 5 microns and more preferably, the diffusionbarrier coat thickness is from about 10 microns to about 50 microns.Optimum coat weight and coat thickness may be determined for eachdrug-resin complex and generally depend on the drug releasecharacteristics of the resin for a particular drug. For example, toachieve drug release times within about 1 hour to about 4 hours, thedrug-resin complex may be coated with a light coat weight. A light coatweight is a coat weight present in the amount of about 10% to about 20%by weight of the dry resin. To achieve drug release times from about 6hours to 10 hours, a medium coat weight may be used, i.e. a coat weightpresent in the amount of 30% to about 35% by weight. To achieve drugrelease times for about 12 hours, a heavy coat weight may be used, i.e.a coat weight of about 40% to 50% by weight of the dry resin.

Triggered-Release Coatings

A water-soluble barrier comprises a pharmaceutically acceptable polymersuch as, for example, methylcellulose (dissolves in cold water),hydroxypropylmethylcellulose (HPMC), hydroxyethlycellulose (HEC),acrylic acid ester, cellulose acetate phthalate, HEC phthalate, HPMCphthalate, hydroxypropyl cellulose (HPC), polyethylene glycol, polyvinylalcohol, xanthan gum, carbomer, carrageenan, zooglan or other cellulosicpolymers, or mixtures of polymers. Drugs mixed with one or more of thesepolymers, or covered by a layer of the polymer, will not be releaseduntil the polymer dissolves or degrades.

Triggered-release coatings are degraded as a result of a triggeringevent. Triggering events may be pH dependent or pH independent. A pHdependent coating is activated to release drug within a known pH range,which typically is matched to the local pH of the environment wheredelayed release is desired. Exemplary pH dependent coatings includecellulose acetate phthalate, cellulose acetate trimellitate,hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate(PVAP), carboxymethylethylcellulose, co-polymerized methacrylicacid/acrylic acid ethyl esters, co-polymerized methacrylicacid/methacrylic acid methyl esters such as, for instance, materialsknown under the trade name EUDRAGIT L12.5, L100, or EUDRAGIT S12.5, S100or similar compounds. Aqueous colloidal polymer dispersions orre-dispersions can be also applied, e.g., EUDRAGIT L 30D-55, EUDRAGITL100-55, EUDRAGIT S100, EUDRAGIT preparation 4110D (Rohm Pharma);AQUATERIC, AQUACOAT CPD 30 (FMC); KOLLICOAT MAE 30D and. 30DP (BASF); orEASTACRYL 30D (Eastman Chemical). Aqueous colloidal polymer dispersionsor re-dispersions can be also applied, e.g. EUDRAGIT® L 30D-55, EUDRAGITL100-55, EUDRAGIT S100, EUDRAGIT preparation 4110D (Rohm Pharma);AQUATERIC®, AQUACOAT CPD 30 (FMC); KOLLICOAT MAE® 30D and 30DP (BASF);EASTACRYL® 30D (Eastman Chemical).

A pH independent coating includes materials susceptible to enzymaticactivation. Exemplary triggered-release coatings include cross-linkedgelatin, polylactic acid, cellophane, plastarch material,polycaprolactone, polyglycolide, poly-3-hydroxybutyrate, zein, materialssusceptible to enzymatic activation by azo-reductases in intestinalbacteria, and materials susceptible to degradation in the colon.

The invention provides for combinations of triggered-release coatingsand diffusion barrier coatings. For example, the invention provides fordrug-resin particles that include a diffusion barrier coating such asethylcellulose which is overcoated with a triggered-release coating (orvice versa, i.e., the triggered-release coating is overcoated with adiffusion barrier coating). This multicoated particle provides for adelayed release (via the triggered-release coating) followed by animmediate or extended release (via the diffusion barrier coating).

Dosage Forms

The invention provides for pharmaceutical compositions comprisingvarious pluralities of drug-resin particles in which the pharmaceuticalcomposition is, for example, a liquid, a chewable composition, or anorally disintegrating solid. Alternatively, pharmaceutical compositionsaccording to this invention may be prepared in capsules or by standardtableting methods. For example, the invention provides for suchpharmaceutical compositions in which (i) the rate of appearance of thedrug (e.g., at least one amphetamine) in a dissolution medium isincreasing during a time period from a first time point through to asecond time point, wherein the first time point is at least one hourafter the composition is introduced into the dissolution medium; and/or(ii) the composition achieves an ascending plasma concentration of thedrug (e.g., at least one amphetamine) after a therapeutic effectivelevel is reached (e.g., one, two, three hours after ingestion of thecomposition).

In any of the dosage forms described herein, the drug may be at leastone of an amphetamine or dextroamphetamine, or methylphenidate. In somepreferred modes, both amphetamine or dextroamphetamine are present.

Liquid Drug Suspensions

The invention provides for liquid oral dosage forms. These dosage formshave distinct advantages over prior art solid dosage forms includingdosage flexibility and ease of swallowing. Liquid dosage forms areespecially preferred for pediatric use.

Liquid oral dosage forms include aqueous and nonaqueous solutions,emulsions, suspensions, and solutions and/or suspensions reconstitutedfrom non-effervescent granules, containing suitable solvents,preservatives, emulsifying agents, suspending agents, diluents,sweeteners, coloring agents, and flavoring agents. Liquid forms, such assyrups and suspensions, preferably contain from about 1% to about 50%,and more preferably from about 1% to about 25%, and most preferably fromabout 3% to about 10%, of the drug-resin complex. Other optionalingredients well known to the pharmacist's art may also be included inamounts generally known for these ingredients, for example, natural orartificial sweeteners, flavoring agents, colorants and the like toprovide a palatable and pleasant looking final product; acidulants, forexample, citric acid, ascorbic acid, or malic acid and the like toadjust pH; antioxidants, for example, butylated hydroxy anisole orbutylated hydroxy toluene; and preservatives, for example, methyl orpropyl paraben or sodium benzoate, to prolong and enhance shelf life.

In preparing the liquid oral dosage forms, the coated drug-resincomplexes are incorporated into an aqueous-based orally acceptablepharmaceutical carrier consistent with conventional pharmaceuticalpractices. An “aqueous-based orally acceptable pharmaceutical carrier”is one wherein the entire or predominant solvent content is water.Typical carriers include simple aqueous solutions, syrups, dispersionsand suspensions, and aqueous based emulsions such as the oil-in-watertype. Preferably, the carrier is a suspension of the pharmaceuticalcomposition in an aqueous vehicle containing a suitable suspendingagent. Suitable suspending agents include Avicel RC-591 (amicrocrystalline cellulose/sodium carboxymethyl cellulose mixtureavailable from FMC), guar gum and the like. Such suspending agents arewell known to those skilled in the art. While the amount of water in thecompositions of this invention can vary over quite a wide rangedepending upon the total weight and volume of the drug-resin complex andother optional non-active ingredients, the total water content, based onthe weight of the final composition, will generally range from about 20to about 75%, and, preferably, from about 20 to about 40%, byweight/volume.

Although water itself may make up the entire carrier, typical liquidformulations may contain a co-solvent, for example, propylene glycol,glycerin, sorbitol solution and the like, to assist solubilization andincorporation of water-insoluble ingredients, such as flavoring oils andthe like, into the composition. In general, therefore, the compositionsof this embodiment preferably contain from about 5 to about 25volume/volume percent and, most preferably, from about 10 to about 20volume/volume percent, of the co-solvent.

Orally Disintegrating and Chewable Dosage Forms

The invention also provides for compositions and methods of makingorally disintegrating or chewable, controlled-release formulations. Inparticular, the invention provides for orally disintegrating andchewable dosage forms comprising the various pluralities of drug-resinparticles described herein Like liquid dosage forms, orallydisintegrating and chewable dosage forms have distinct advantages overprior art solid dosage forms including ease of ingestion. Methods ofpreparing orally disintegrating and chewable dosage forms withdrug-resins are known in the art. See U.S. Publication No. 2007/0092553,which is hereby incorporated by reference in its entirety.

Drug Release Profiles

The invention provides for compositions having various drug (e.g., ADHDeffective agent) release profiles. In particular, the compositions maybe administered in the morning and have therapeutically effectiveactivity throughout the course of the day. For example, in oneembodiment, the composition is administered to a child during breakfast(i.e., before school starts) and, by the time school starts, the ADHDeffective agent (e.g., amphetamine, methylphenidate) will begin having atherapeutic effect on the child. The composition will continue to betherapeutically effective throughout the day including themid-afternoon, when children tend to be fatigued. As such, thecompositions described herein have an escalating in vivo serum profile.

In some embodiments, the invention provides for compositions in whichthe rate of appearance of the ADHD effective agent (e.g., at least oneamphetamine) in a dissolution medium increases after a period ofdecrease in the rate of appearance of the drug in the dissolutionmedium. The compositions typically contain an immediate release anddelayed release portion. The immediate release portion, in an in vitrodissolution assay, contributes to an initial release of ADHD effectiveagent (e.g., 30-60%) within an initial time period (e.g., 0.5, 1, 1.5,2, or 2.25 hours from when the composition is introduced into thedissolution medium). After the initial increase amount of ADHD effectiveagent in the dissolution, due to the immediate release portion, therelease rate of ADHD effective agent will decrease or level off. Afterthis decrease or leveling off, typically the delayed release portionwill release and the amount of ADHD effective agent released increasesuntil, e.g., 80% or more of the ADHD effective agent is released. Itwill be appreciated that the first and second time points will varydepending on the ADHD effective agent, coatings used, and ratio ofimmediate and delayed release drug-resin particles.

In a particular embodiment, 40-45% of the drug (e.g., ADHD effectiveagent such as at least one amphetamine) is released within the first 45minutes after the drug-resin particles are introduced into a dissolutionassay, followed by a period of substantially no drug release from 45minutes to 2 hours, and concluding with period of from 2 to 8 hours inwhich substantially all of the remaining ADHD effective agent isreleased from 2 to 8 hours. In another embodiment, 40-45% of the drug(e.g., ADHD effective agent such as at least one amphetamine) isreleased within the first 45 minutes after the drug-resin particles areintroduced into a dissolution assay, 45-50% of the drug is releasedwithin 45 minutes to 2 hours, and 50-100% of the drug is released within2 to 8 hours. In another embodiment, the delayed release coatingreleases substantially all of the one or more pharmaceutically activeADHD effective agents (e.g., amphetamines) coated with the delayedrelease coating within about 60 minutes after initiation of the delayedrelease. In yet another embodiment, 30-33% of the drug (e.g., ADHDeffective agent such as methylphenidate) is released the first 30minutes after the drug-resin particles are introduced into a dissolutionassay, 34-42% of the drug is released within 30 minutes to 2 hours,40-80% of the drug is released within 2 to 4 hours and 80-100% of thedrug is released within 4 to 24 hours. For any of these embodiments, theconditions of the dissolution assay may be an initial dissolution mediumof 0.1 N HCL, and after 2 hours, the medium is adjusted to a pH whichtriggers the triggered release coating, e.g., pH of ˜6.8; anddissolution testing is performed using a USP Apparatus 2. In otherembodiments, the pH is adjusted to e.g., pH 6.8, 7, etc.

The invention also provides for compositions in which the compositionachieves an ascending plasma concentration of the drug (e.g., at leastone amphetamine during a time period) after a therapeutically effectivelevel is reached. Typically, a therapeutically effective level isreached within one, two, three, four, or five hours after ingestion ofthe composition. Sometime after the therapeutically effective level isreached, the plasma concentration of drug increases due to additionalrelease of drug from the drug-resin complex in the composition to a peakdrug concentration level. In some individuals, clearance of drug willresult in a decrease in plasma level between these two releases,resulting in two successive peak drug levels. In others, the timing ofthe two releases is close enough that no decrease is observed. As aresult, the in vivo plasma concentration profile is preferably bimodalwith two peaks. For example, the first peak may be achieved, between 1to 3, 1 to 2.5, or 1 to 2 hours after ingestion of the composition. Thesecond peak may be achieved 4 to 7, 4 to 6, or 4 to 5 hours afteringestion of the composition. The first or second peak may be theC_(max). Alternatively, the composition may have an in vivo serumprofile that reaches a therapeutically effective level fairly rapidly(1-3 hours) and them continues to increase more slowly up to a maximumserum level between 4 hours and 7 hours after ingestion. It will beappreciated that the therapeutic and peak drug concentration level willvary depending on the subject, drug, coatings used, and ratio ofimmediate and delayed release drug-resin particles.

The compositions of the invention may include at least one plurality ofdrug-resin particles coated with a triggered-release coating. In aparticular embodiment, the invention provides for a first plurality ofuncoated drug-resin particles and a second plurality of drug-resinparticles being coated with a triggered-release coating. In anotherembodiment, the invention provides for a first plurality of uncoateddrug-resin particles, a second plurality of drug-resin particles beingcoated with a triggered-release coating, and a third plurality ofdrug-resin particles being coated with a diffusion barrier coating. Inanother embodiment, the composition is a liquid dosage form and includesat least one plurality of drug-resin particles being coated with atriggered-release coating accompanied by unbound drug in solution.

Any of the diffusion barrier coatings or triggered-release coatingsdescribed herein may be used in any of the dosage forms describedherein. For example, the some embodiments, the triggered-release coatingis EUDRAGIT L100 or EUDRAGIT L100-55. In some embodiments, thetriggered-release coating may have an overcoat (e.g., HPMC).

In other embodiments, the drug-resin particles may comprise both atriggered-release and a diffusion barrier coating. For example, thetriggered-release coating may cover (i.e., overcoat) the diffusionbarrier coating. In one embodiment, the diffusion barrier coating isethylcellulose and the triggered-release coating is polyvinyl acetatephthalate (PVAP).

The invention provides pharmaceutical compositions comprising variousmixtures of immediate release drug-resin particles (e.g., uncoateddrug-resin particles) and delayed release drug-resin particles (e.g.,triggered-release coated drug-resin particles). In one embodiment, thepharmaceutical composition comprises 20%-50% of immediate releasedrug-resin particles and 50-80% of delayed release drug-resin particles.In a particular embodiment, the composition comprises 40%-50% ofimmediate release drug-resin particles and 50%-60% of delayed releasedrug-resin particles. In a specific embodiment, the pharmaceuticalcomposition comprises 45% of immediate release drug-resin particles and55% of delayed release drug-resin particles. In another embodiment, thecomposition comprises 20%-30% of immediate release drug-resin particlesand 70%-80% of delayed release drug-resin particles. In a specificembodiment, the pharmaceutical composition comprises 25% of immediaterelease drug-resin particles and 75% of delayed release drug-resinparticles. As shown in the Examples, the percentage of uncoated andcoated particles, as well as the types and percentages of coatings,effects the release profiles of the drug (e.g., at least oneamphetamine).

The Examples provide in vitro dissolution and in vivo serum profiles forexemplary compositions of the inventions. These compositions (and theirprofiles) are encompassed within the invention. It will be understoodthat complete and partial profiles (e.g., partial AUCs) of thecompositions set forth and described in the Examples are encompassedwithin the invention.

In one embodiment, the invention provides for administering an effectiveamount of a ADHD effective agent (e.g., at least one amphetamine such asa mixture of levo-amphetamine and dextroamphetamine). The effectivedosage may range from 3.13 mg of amphetamine calculated as free base(equivalent to 5 mg of mixed amphetamine salts found in ADDERALL XR) to18.8 mg of amphetamine calculated as free base (equivalent to 30 mg ofmixed amphetamine salts found in ADDERALL XR). The amphetamine providedis preferably a mixture of 75% dextroamphetamine and 25%levoamphetamine. A delivery of about 2 mg/24 hours to about 60 mg/24hours of the compositions of the invention, and more preferably fromabout 5 mg/24 hours to about 30 mg/24 hours, is typically needed toachieve a therapeutically effective dose in a patient (based on mixedamphetamine salts in ADDERALL XR). In particular embodiments, children6-12 years old may take 10-30 mg/day (e.g., 0.5 mg/kg/day to 1.5mg/kg/day), adolescents 13-17 years old may take 10-20 mg/day (0.25mg/kg/day to 0.5 mg/kg/day), and adults may take 20 mg/day (0.28/kg/dayto 0.4 mg/kg/day) (based on a mixed amphetamine salt in ADDERALL XR).

In another embodiment, the invention provides for administering aneffective amount of methylphenidate. In one embodiment, the effectivedosage ranges from 8.7 mg of methylphenidate base (equivalent to 10 mgof methylphenidate HCl) to 52.2 mg of methylphenidate base (equivalentto 60 mg of methylphenidate HCl). In another embodiment, the effectivedosage is 26.1 mg of methylphenidate base (equivalent to 30 mg ofmethylphenidate HCl). A delivery of about 10 mg/24 hours to about 60mg/24 hours of the compositions of the invention, and more preferablyfrom about 20 mg/24 hours to about 40 mg/24 hours, is typically neededto achieve a therapeutically effective dose in a patient (based onmethylphenidate HCl).

The compositions may be administered once-a-day (e.g., in a single unitor multiple unit compositions) in an amount that provides a therapeuticbenefit equivalent to multiple doses of immediate release dosages.

The invention also provides for unit doses and packaging comprising unitdosages. For example, the invention provides for individually packagedliquid drug suspensions (e.g., 5, 10, 15, 30, or 60 ml), or theequivalent amount of drug as a chewable compositions or orallydisintegrating dosage forms described herein. Methods of preparing unitdosage forms are known in the art.

It will be understood that the various aspects described herein may becombined. For example, the invention provides for a pharmaceuticalcomposition comprising a first plurality of drug-resin particles beinguncoated and a second plurality of drug-resin particles being coatedwith a triggered-release coating, wherein the drug is an ADHD effectiveagent (e.g., at least one amphetamine, methylphenidate) and the resin isIRP-64, IRP-69, IRP-88, or AP143.

Methods of Making Dosage Forms

The invention provides for methods of making the pharmaceuticalcompositions described herein. In one embodiment, the method comprises(a) loading a plurality of resin particles with at least one ADHDeffective agent (e.g., at least one amphetamine, methylphenidate) toform drug-resin particles; (b) coating a subset of the loaded drug-resinparticles with a delayed release coating (e.g., triggered-releasecoating) to form coated drug-resin particles; and (c) combining a subsetof loaded, uncoated drug-resin particles with coated drug-resinparticles in a pharmaceutical composition. In another embodiment, themethod comprises (a) loading a plurality of resin particles with atleast one ADHD effective agent (e.g., at least one amphetamine,methylphenidate) to form drug-resin particles; (b) coating drug-resinparticles with a delayed release coating (e.g., triggered-releasecoating) to form coated drug-resin particles; and (c) combining saiddrug-resin particles with said coated drug-resin particles in apharmaceutical composition.

In another embodiment, the method involves (a) loading a plurality ofresin particles with an ADHD effective agent (e.g., methylphenidate) toform drug-resin particles; (b) coating drug-resin particles with anextended release coating (e.g., ethyl cellulose) to form extendedrelease coated drug-resin particles; (c) further coating the extendedrelease coated drug-resin particles with a delayed release coating(e.g., triggered-release coating) to form extended release/delayedrelease coated drug-resin particles; and (d) combining loaded, butuncoated drug-resin particles with the extended release/delayed releasecoated drug-resin particles in a pharmaceutical composition. In analternative embodiment, a delayed release coating is applied to theloaded drug-resin particles to form delayed release coated drug-resinparticles, and the extended release coating is then applied to thedelayed release coated drug-resin particles.

The compositions made by the methods described herein may comprisevarious pluralities of drug-resin particles with the profiles describedherein. For example, the composition may comprise pluralities ofdrug-resin particles such that (i) the rate of appearance of the drug(e.g., at least one amphetamine) in a dissolution medium is increasingduring a time period from a first time point through to a second timepoint, wherein the first time point is at least one hour after thecomposition is introduced into the dissolution medium; and/or (ii) thecomposition achieves an ascending plasma concentration of the drug(e.g., at least one amphetamine) after a therapeutic effective level isreached (e.g., one, two, three hours after ingestion of thecomposition).

Methods of loading drugs onto resin particles are generally known in theart. The invention provides for methods of loading ADHD effective agents(e.g., at least one amphetamine, methylphenidate) onto resin particles(e.g., IRP-69, IRP-64, IRP-88, AP143). An exemplary method of loading isdepicted in FIG. 1 and described in Example 1. In another embodiment,the composition comprises drug-resin particles comprise a mixture of l-and d-amphetamine (e.g., 25% l-amphetamine and 75% d-amphetamine),wherein each enantiomer is loaded onto a separate resin and theseparately loaded resins are combined to form drug-resin particles.Alternatively, l- and d-amphetamine are mixed together in the desiredratio (e.g., 25% l-amphetamine and 75% d-amphetamine) and the mixedamphetamines are then loaded onto resins to form drug-resin particles.

Methods of coating drug-resin particles are also generally known in theart. The invention provides for various coating solutions andcombinations of coatings (e.g., triggered-release coating such asEUDRAGIT L100, and a combination of EUDRAGIT 100 with HPMC). Example 2provides an exemplary coating process and Examples 4-9 provide exemplarycompositions with different coatings. Coatings may be applied usingmethods known in the art, such as with a fluid-bed coating apparatushaving the Wurster configuration.

In alternative embodiments, the invention provides for methods of makingorally disintegrating and chewable dosage forms comprising the variouspluralities described herein. Methods of preparing orally disintegratingand chewable dosage forms with drug-resins are known in the art. SeeU.S. Publication No. 2007/0092553, which is hereby incorporated byreference in its entirety.

It will be understood that the various aspects described herein may becombined. For example, the invention provides for a pharmaceuticalcomposition comprising a first plurality of drug-resin particles beinguncoated and a second plurality of drug-resin particles being coatedwith a triggered-release coating, wherein the drug is at least oneamphetamine or methylphenidate and the resin is IRP-64, IRP-69, IRP-88,AP143.

Methods of Treatment

The invention provides for various methods of treatment using the dosageforms described herein. In a particular embodiment, the inventionprovides for methods of treating ADD or ADHD, fatigue, obesity, or forimparting alertness, comprising administering an effective amount of anyof the compositions described herein (e.g., a composition comprising atleast one plurality of drug-resin particles being uncoated and at leastone plurality of drug-resin particles coated with a delayed releasecoating such as a triggered-release coating, where the drug is at leastone ADHD effective agent and the composition is, for example, a liquid,a chewable composition, or an orally disintegrating solid). In apreferred method, the individual being treated suffers from dysphagia.

It will be understood that the various aspects described herein may becombined. For example, the invention provides for methods of treatingADD or ADHD comprising administering an effective amount of apharmaceutical composition comprising a first plurality of drug-resinparticles being uncoated and a second plurality of drug-resin particlesbeing coated with a triggered-release coating, wherein the drug is atleast one amphetamine or methylphenidate and the resin is IRP-64,IRP-69, IRP-88, AP143.

Methods of Reducing Exposure of Amphetamines

The inventors have observed that, when the compositions described hereinare administered to a subject substantially contemporaneously withethanol, the subject has a reduced exposure level of an ADHD effectiveagent (e.g., amphetamines) compared to administering a reference listeddrug (e.g., ADDERALL XR) to a subject substantially contemporaneouslywith ethanol. In particular embodiments, the exposure of amphetaminesare reduced within 1.0, 1.5, 2.0, 2.5, and/or 3.0 hours after ingestionof the composition and ethanol. As such, the invention relates tomethods of reducing exposure of amphetamines and, in particular, reducedexposure levels as compared to ADDERALL XR. The reduction in exposure isdetectable; and assays for detecting exposure levels and comparingexposure levels are known in the art.

The inventors also observed that, when the compositions described hereinare introduced into a dissolution medium substantially contemporaneouslywith ethanol, dose dumping of an ADHD effective agent (e.g.,amphetamines) is reduced compared to introducing a reference listed drug(e.g., ADDERALL XR) into the same dissolution medium substantiallycontemporaneously with ethanol. As such, the invention relates tomethods of reducing dose dumping of amphetamines in vitro and, inparticular, reduced dose dumping as compared to ADDERALL XR. Thereduction in dose dumping is detectable; and assays for detecting dosedumping levels and comparing such levels are known in the art. Forexample, cumulative release in vitro may be measured for the initialportion of the release curve, e.g., the first 0.5, 1, 1.5, 2, or 3hours. Dose dumping may be evaluated from a partial area under the curvemeasurement to a relevant time point.

Dosage Forms Bioequivalent to a Target Product

The invention provides for dosage forms, methods of making dosage forms,and methods of administering dosage forms (e.g., for the conditionsdescribed herein such as ADHD) that are bioequivalent to a targetproduct. In various embodiments, the invention provides for dosage forms(e.g., a liquid drug suspension, orally disintegrating tablet) that arebioequivalent to the in vivo serum profile of ADDERALL XR, or METADATECD methods of making such dosage forms, and methods of treatment (asdescribed herein) using such dosage forms. In particular embodiments,the compositions have complete and/or partial profiles (e.g., partialAUCs) that are bioequivalent to the profiles of ADDERALL XR or METADATECD. Examples 16 and 17 describe such compositions. For example, theinvention encompasses compositions that, when administered to a human,produce a mean plasma concentration profile which has any one of AUC₀₋₃,AUC₀₋₄, AUC₀₋₅, AUC_(0-max), AUC₄₋₁₂, AUC₅₋₁₂, AUC_(tmax-12), AUC₅₋₂₄,AUC_(tmax-24), AUC_(5-t), AUC_(tmax-t) AUC₀₋₂₄ and/or AUC_(0-∞) (e.g.,at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 and/or 13 AUC values) thatis/are bioequivalent to the corresponding profiles of ADDERALL XR orMETADATE CD.

U.S. Pat. Nos. 6,322,819 and 6,605,300, which are hereby incorporated byreference in their entirety, provide release profiles and plasmaconcentrations of ADDERALL XR. See also FIG. 23.

In another embodiment, the invention provides for dosage forms (e.g.,orally disintegrating tablet) that are statistically similar and/or havepartial AUCs with 90% confidence intervals that are within 80-125% ofMETADATE CD. For example, Example 18 describes compositions in whichd-methylphenidate and total methylphenidate (d+l) are statisticallysimilar and/or have AUC_(last) and AUC_(inf) with 90% confidenceintervals that are within 80-125% of METADATE CD; but which does nothave T_(max) that is substantially similar.

EXAMPLES

The following examples describe various compositions encompassed withinthe invention and their corresponding dissolution and in vivo serumprofiles. These examples are not intended to limit the invention in anyway.

Example 1 Loading the Resin Particles with Drug

The invention relates pharmaceutical compositions comprising drug-resinparticles and the methods of making these compositions. This exampleprovides an exemplary method of loading amphetamines onto resinparticles. FIG. 1 depicts this loading method.

In a kettle, amphetamine sulfate and dextroamphetamine sulfate are mixedin purified water until fully dissolved. AMBERLITE IRP 69 resins areadded to the kettle and mixed. The solution is filtered through a 20 μmfilter (Grade 54), then again through a 8 μm filter (Grade 540). Theloaded resinate is collected on the filter paper during each filtration.

In a kettle, polyethylene glycol is mixed in purified water until fullydissolved. After it is completely dissolved, the loaded resinate isadded, and the solution is mixed until uniform. The solution is filteredthrough a 20 μm filter (Grade 54), then again through a 8 μm filter(Grade 540). The loaded resinate/PEG is collected on the filter paperduring each filtration.

The loaded resinate/PEG is dried in an oven until Loss on Drying isbetween 3% and 7%. The dried material is screened through a 100-mesh and325-mesh screen.

The material that passed through the 100-mesh screen, but did not passthrough the 325-mesh screen, is collected. This material is used as theuncoated delayed release resinate. Alternatively, this material could beused as a substitute immediate release resinate.

The material that did not pass through the 100-mesh screen is milledusing a Fitzmill (with knives forward and a 50-mesh screen). Thismaterial is added together with the material that passed through the325-mesh screen to become the immediate release resinate. These twomaterials are blended together.

Example 2 Coating Drug-Resin Particles

The pharmaceutical compositions of the invention may comprise a coatedand uncoated plurality of drug-resin particles. The coated drug-resinparticles provide the delayed or triggered-release portion of thecomposition. This example provides an exemplary method of preparing apolymer coating for the coated drug-resin particles.

A clean, stainless steel container is pre-weighed. Acetone and ethanolare added to the container. Plasticizer is then added to the containerand mixed until dispersed. A coating polymer such as HPMC, is slowlyadded to the container while mixing. The polymer solution iscontinuously stirred for at least an hour and until all of the solidsare dissolved. This coating solution is continuously stirred during thecoating process. The loaded resinate of Example 1 may be coated (e.g.,in a wurster coater) with this coating solution to prepare coateddrug-resin complexes.

Example 3 Loading Resin Particles with Drug and Coating the Drug-ResinParticles

The methods of Examples 1 and 2 may be combined to prepare thepharmaceutical compositions of the invention. In particular, drug-resinparticles may be prepared using the method of Example 1, and thosedrug-resin particles to be used as the delayed release portion of thecomposition may be coated with a polymer coating prepared by the methodof Example 2. The particles may be dried and mixed in a V-blender. Thespecific ratio of immediate release and delayed release particles mayvary as described below.

Once the resin particles are loaded, coated, and mixed, the resultingdrug-resin particles may be used in any suitable dosage form (e.g.,suspension, chewable composition, orally disintegrating composition,capsule, tablet, etc.).

Example 4 Orally Disintegrating Tablet with 45% IR and 55% DR (FormulaA)

An orally disintegrating tablet was formulated with 45% of theamphetamine from immediate release resin complex and 55% of theamphetamine from a delayed release resin complex. A hydroxypropylmethylcellulose (HPMC) coating overlays the delayed released resincomplex. The formula is presented below in Table 1.

TABLE 1 ODT amphetamine formulation with 45% IR and 55% DR with HPMCOvercoat

IR - 34.17% base assay & DR - 6.26% base assay: These values will bevariable.

Dissolution Method

Dissolution Parameters:

Dissolution testing is carried out using a USP Apparatus 2 with cannulasand cannula filters (Quality Lab Accessories, Porus Micron full flowfilters 20 micron); paddle speed—100 rpm; kettle size—1000 mL;temperature—37.0±0.5° C.; filter—25 mm 0.45 um PVDF w/GMF; syringe—B-D10mL Luer-Lok.

Dissolution Media:

The medium for the dissolution assay is 900 mL of 0.1N HCl for the firsthour; after 2 hour time point ˜100 mL of potassium phosphate/sodiumhydroxide solution is added to bring to pH ˜6.8.

The sample is weighed and is placed into the corresponding kettle, andthe dissolution timing started.

Sampling pull times are 30 minutes, 1 hour, 2 hours, 3 hours, and 4hours. For each sample pull time and each kettle, 10 mL of sample arepulled into a B-D 10 mL Luer-Lok syringe and returned to the kettlesbefore the sample pull to flush out the cannula from the prior pulls. 2ml are then pulled for filtration and placed into an HPLC vial.Non-media replacement and volume changes from the two media changes arecalculated.

Dissolution Profile:

The amount of drug in the filtrate at each time point is determined byHPLC, and the percentage released from the drug-resin is plotted in FIG.2.

The same profile was obtained without the use of the HPMC overcoat.

Example 5 Orally Disintegrating Tablet with 30% IR and 70% DR (FormulaB)

An orally disintegrating tablet was formulated with 30% of theamphetamine from immediate release resin complex and 70% of theamphetamine from a delayed release resin complex. An HPMC coatingoverlays the delayed released resin complex. The formula is presented inTable 2.

TABLE 2 ODT amphetamine formulation with 30% IR and 70% DR with HPMCOvercoat

IR - 34.17% base assay & DR - 6.26% base assay: These values will bevariable.

The dissolution method is performed as described in the previousExample, except that sample pull times are 0.5, 1.0, 1.5, 2.0, 3.0, 4.0,5.0, and 6.0 hours.

Dissolution Profile:

The amount of drug in the filtrate at each time point is determined byHPLC, and the percentage released from the drug-resin is plotted in FIG.3.

The same profile was obtained without the use of the HPMC overcoat.

Example 6 Orally Disintegrating Tablet with 45% IR and 55% DR (FormulaC)

An orally disintegrating tablet was formulated with 45% of theamphetamine from immediate release resin complex and 55% of theamphetamine from a delayed release resin complex. This formulation didnot include an HPMC overcoat. The formula is presented in Table 3.

TABLE 3 ODT amphetamine formulation with 45% IR and 55% DR

IR - 34.17% base assay & DR - 8.53% base assay: (These values will bevariable).

The dissolution method is performed as described in Example 4, exceptthat sample pull times are 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0,and 8.0 hours.

Dissolution Profile:

The amount of drug in the filtrate at each time point is determined byHPLC, and the percentage released from the drug-resin is plotted in FIG.4.

Example 7 Suspension with 50% IR and 50% DR (Formula A1)

A suspension was formulated with 50% of the amphetamine from immediaterelease resin complex and 50% of the amphetamine from a delayed releaseresin complex. The resin was IRP-69. The delayed release resin complexescoated with 15% TEC, and 70% EUDRAGIT L100. The formulation is presentedin Table 4.

TABLE 4 Suspension amphetamine formulation with 50% IR and 50% DRIngredient Application Amount per 15 ml Purified Water Diluent 7.9 gAscorbic Acid pH 6.00 mg Propylene Glycol Solvent 525.00 mgMethylparaben Preservative 12.00 mg Propylparaben Preservative 1.50 mgPolysorbate 80 Surfactant 15.00 mg Xanthan Gum Suspending Agent 90.00 mgVegetable (Corn) Oil Viscosity Agent 30.00 mg Amphetamine Active Resin27.57 mg Uncoated Resin Amphetamine Active Resin 76.19 mg Coated ResinSucrose Sweetener 2250.00 mg High Fructose Corn Syrup Sweetener 6750.00mg

The dissolution method was performed as described in Example 4, exceptthat the samples were pulled at different time points: 0.5, 1.0, 1.5,2.0, 2.5, 3.0, 4.0, and 6.0 hours.

Dissolution Profile:

The amount of drug in the filtrate at each time point was determined byHPLC, and the percentage released from the drug-resin is plotted in FIG.5 and reflected below.

2 W 2 W Leakage Initial AMB¹ ASL² 30 Mins (% Release): 47.9 56.8 60.3 @2 Hours 51.5 67.2 72.4 (% Release): Profile (% Release) Hours 0.5 47.956.8 60.3 1 51.5 66.7 70.5 1.5 52.2 66.1 72.5 2 52.8 67.2 72.4 2.5 93.4100.2 97.8 3 94.9 99.9 97.8 4 95.6 100.1 98.1 6 102.5 98.2 ¹Two weeksunder ambient conditions. ²Two weeks under accelerated shelf lifeconditions.

Example 8 ODT with 50% IR and 50% DR (Formula D)

An orally disintegrating tablet was formulated with 50% of theamphetamine from immediate release resin complex and 50% of theamphetamine from a delayed release resin complex. This formulation wassimilar to Examples 4-6 and is reflected in Table 5. The resin wasIRP-69. The delayed release coated resin comprised 15% TEC, and 70%EUDRAGIT L100.

TABLE 5 ODT amphetamine formulation with 50% IR and 50% DR. Amount perIngredient Application tablet Amphetamine Resin IR Active Resin I 38.10mg (Assay-16.9%) Amphetamine Resin DR Active Resin II 13.79 mg(Assay-46.7%) Ludiflash Compressing 371.11 mg  Agent CroscarmelloseSodium Disintegrant 22.50 mg Magnesium Stearate Lubricant  4.50 mg

The dissolution method was performed as described in Example 4, exceptthat the samples were pulled at different time points.

Dissolution Profile:

The amount of drug in the filtrate at each time point was determined byHPLC, and the percentage released from the drug-resin is plotted in FIG.6 and reflected below.

Profile (% Release) Hours 0.5 50.5 1 51.0 1.5 51.5 2 52.4 2.5 85.3 396.0 4 96.9

Example 9 ODT with 35% IR and 65% DR (Formula E)

An orally disintegrating tablet was formulated with 35% of theamphetamine from immediate release resin complex and 65% of theamphetamine from a delayed release resin complex. This formulation wassimilar to Examples 4-6 and is reflected in Table 6. Unlike theseexamples, however, the resin was an IRP-64 resin. The delayed releasecoated resin comprised 15% HPMC, 15% TEC, and 110% EUDRAGIT L100.

TABLE 6 ODT amphetamine formulation with 35% IR and 65% DR with HPMCOvercoat Amount per Ingredient Application tablet Amphetamine Resin DRActive Resin I 128.8 mg¹ (Assay-6.5%) Amphetamine Resin IR Active ResinII 7.07 mg² (Assay-63.73%) Ludiflash Compressing 287.13 mg AgentCroscarmellose Sodium Disintegrant 22.50 mg Magnesium Stearate Lubricant4.50 mg

The dissolution method was performed as described in Example 4, exceptthat the samples were pulled at different time points.

Dissolution Profile

The amount of drug in the filtrate at each time point was determined byHPLC, and the percentage released from the drug-resin is plotted in FIG.7 and reflected below.

Profile (% Release) Hours 0.5 47.6 1 52.4 1.5 56 2 58.2 2.5 81.8 3 88.94 93.4 24 108.3

Example 10 pH Study

A pH study was also conducted to compare a control and four differentcoated drug-resin particles prepared according to the methods describedin Examples 1 and 2 for the following coatings and resins: (1) 70%EUDRAGIT L100/IRP69; (2) 110% EUDRAGIT L100/IRP 64; (3) 40% EUDRAGITL100-55/IRP 69; (4) 70% EUDRAGIT L100-55/IRP 64.

pH Study Protocol:

The medium for the dissolution assay is 0.1N HCl. pH change bufferdescribed in the previous examples is added, drop wise, until a pH of2.0, 3.0, 4.0, 5.0, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1,6.2, and 6.5 is reached. At each pH point, 2 mL of sample was removedand then pH change buffer solution is added to adjust pH to next pHtarget. The next sample is taken 10 minutes after adjusted pH.

Varying the coating and the resin composition shifted the release curveas shown in FIG. 8. EUDRAGIT L100 and IRP69 gave results closest to thepH for release observed with ADDERALL XR.

Example 11 Pig Study Using Pharmaceutical Compositions

This study is an open-label, random order, crossover comparison study ofthree test formulations (two tablets and one liquid suspension) and thecurrently marketed reference drug (ADDERALL XR). In vivo studies areperformed using pigs. A total of 12 animals are initially assigned tostudy (3 males per group×4 groups). All animals are fasted overnightprior to dosing and through the first 4 hours of blood sample collection(total fasting time not to exceed 24 hours). Water is available adlibitum. Animals are dosed on days 1, 4, 8, and 15).

Phase 1:

Each animal in Groups 1 and 2 receives a 2 tablet dose of theappropriate test article formulation as outlined in the study design inTable 7 below. Each animal in Group 4 receives a 1 capsule dose of thereference formulation as outlined in Table 7. A balling gun may be used,if appropriate, to facilitate dosing. Whether animals are hand-dosed ora balling gun is used for dosing, a subsequent 10 mL tap water rinse isadministered orally following dosing. Each animal in Group 3 receives asingle oral gavage (PO) dose of the appropriate test article formulationas outlined in the study design table below. The dosing syringes areweighed when loaded with the test formulation and then again followingdose administration for each animal (i.e. loaded and delivered syringeweights). Oral gavage dosing formulations will be continuously stirredthroughout dosing. The gavage tube should be rinsed with approximately10 mL of tap water following dosing (prior to removal of the gavagetube).

Phase 2:

Following a washout at least 3 days, each animal in Groups 2 and 3receives a 2 tablet dose of the appropriate test article formulation asoutlined in Table 7. Each animal in Group 1 receives a 1 capsule dose ofthe reference formulation as outlined in Table 7. A balling gun may beused, if appropriate, to facilitate dosing. Whether animals arehand-dosed or a balling gun is used for dosing, a subsequent 10 mL tapwater rinse is administered orally following dosing. Each animal inGroup 4 receives a single oral gavage (PO) dose of the appropriate testarticle formulation as outlined in the study design table below. Thedosing syringes should be weighed when loaded and then again followingdose administration for each animal (i.e. loaded and delivered syringeweights). Oral gavage dosing formulations should be continuously stirredthroughout dosing. The gavage tube should be rinsed with approximately10 mL of tap water following dosing (prior to removal of the gavagetube).

Phase 3:

Following a washout of at least 3 days, each animal in Groups 3 and 4receives a 2 tablet dose of the appropriate test article formulation asoutlined in Table 7. Each animal in Group 2 receives a 1 capsule dose ofthe reference formulation as outlined in Table 7. A balling gun may beused, if appropriate, to facilitate dosing. Whether animals arehand-dosed or a balling gun is used for dosing, a subsequent 10 mL tapwater rinse is administered orally following dosing. Each animal inGroup 1 receives a single oral gavage (PO) dose of the appropriate testarticle formulation as outlined in the study design table below. Thedosing syringes are weighed when loaded and then again following doseadministration for each animal (i.e. loaded and delivered syringeweights). Oral gavage dosing formulations are continuously stirredthroughout dosing. The gavage tube is rinsed with approximately 10 mL oftap water following dosing (prior to removal of the gavage tube).

Phase 4:

Following a washout of at least 3 days, each animal in Groups 1 and 4receives a 2 tablet dose of the appropriate test article formulation asoutlined in Table 7. Each animal in Group 3 receives a 1 capsule dose ofthe reference formulation as outlined in Table 7. A balling gun may beused, if appropriate, to facilitate dosing. Whether animals arehand-dosed or a balling gun is used for dosing, a subsequent 10 mL tapwater rinse is administered orally following dosing. Each animal inGroup 2 receives a single oral gavage (PO) dose of the appropriate testarticle formulation as outlined in the study design table below. Thedosing syringes are weighed when and then again following doseadministration for each animal (i.e. loaded and delivered syringeweights). Oral gavage dosing formulations are continuously stirredthroughout dosing. The gavage tube is rinsed with approximately 10 mL oftap water following dosing (prior to removal of the gavage tube).

TABLE 7 Pig study design. Number of Dose Dose Level Dose Volume/ MatrixGroup Test Article Males* Route (mg) Amount Collected PHASE 1 1 Neos 2Formulation #1 3 Oral, tablet 30 2 tablets Blood^(E) (15 mg/tablet) 2Neos 2 Formulation #2 3 Oral, tablet 30 2 tablets Blood^(E) (15mg/tablet) 3 Neos 2 Formulation #3 3 PO, Liquid 30 15 mL Blood^(E)suspension 4 Reference Drug 3 Oral, 30 1 capsule Blood^(E) (ADDERALL XR)capsule (30 mg/capsule) Formulation PHASE 2 1 Reference Drug 3 Oral, 301 capsule Blood^(E) (ADDERALL XR) capsule (30 mg/capsule) Formulation 2Neos 2 Formulation #1 3 Oral, tablet 30 2 tablets Blood^(E) (15mg/tablet) 3 Neos 2 Formulation #2 3 Oral, tablet 30 2 tablets Blood^(E)(15 mg/tablet) 4 Neos 2 Formulation #3 3 PO, Liquid 30 15 mL Blood^(E)suspension PHASE 3 1 Neos 2 Formulation #3 3 PO, Liquid 30 15 mLBlood^(E) suspension 2 Reference Drug 3 Oral, 30 1 capsule Blood^(E)(ADDERALL XR) capsule (30 mg/capsule) Formulation 3 Neos 2 Formulation#1 3 Oral, tablet 30 2 tablets Blood^(E) (15 mg/tablet) 4 Neos 2Formulation #2 3 Oral, tablet 30 2 tablets Blood^(E) (15 mg/tablet)PHASE 4 1 Neos 2 Formulation #2 3 Oral, tablet 30 2 tablets Blood^(E)(15 mg/tablet) 2 Neos 2 Formulation #3 3 PO, Liquid 30 15 mL Blood^(E)suspension 3 Reference 3 Oral, 30 1 capsule Blood^(E) (ADDERALL XR)capsule (30 mg/capsule) Formulation 4 Neos 2 Formulation #1 3 Oral,tablet 30 2 tablets Blood^(E) (15 mg/tablet) ^(D) Reference Formulationis a Marketed Product. All capsules and tablets will be used asreceived. ^(E)Blood samples will be collected predose and atapproximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 12, 16, and 24 hours postdose.*The same animals will be used for each phase following a washout of atleast 3 days.

For each phase, blood samples (approximately 2 mL/sample) are collectedfrom the thoracic inlet (jugular vein, or other suitable vein) predoseand at approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 12, 16, and 24 hourspostdose and placed into tubes containing K₂EDTA. All blood samples areplaced on an ice block (or wet ice) following collection. The samplesare centrifuged and the resulting plasma is separated and stored frozenat approximately −70° C. until analyzed (following separation; theplasma may be initially placed on dry ice prior to being stored in the−70° C. freezer). Any clotted samples should be noted.

Plasma samples are analyzed for amphetamine over the range of 0.1 ng/mLto 200 ng/mL. Control plasma procured from a commercial source is usedfor all analyses. Each analysis batch includes duplicate calibrationsamples (one set run at beginning of batch and one at the end of batch)with a minimum of 6 non-zero levels, and duplicate QC samples preparedat 4 concentration levels. The calibration and QC samples are preparedfrom separate stocks. Acceptance criteria for each batch is that atleast 75% of individual calibration points and 62.5% of the QC samplesmust be within +/−30% of the target concentration.

Example 12 In Vivo Study

Drug samples from Examples 4 and 5 were administered to pigs asdescribed in Example 11. Capsules of ADDERALL XR were administered ascontrols under the same conditions.

Results of the pig study are depicted in FIG. 9. Outliers were excluded.FIG. 9 shows the plasma concentrations of drug released from theformulas in Examples 4 and 5 compared to ADDERALL XR (i.e., thereference formulation). The relative amounts of coated and uncoatedparticles differed between Examples 4 and 5; both compositions showedtwo peaks in the in vivo release profile, but with the compositionhaving relatively more coated particles, the T_(max) for both peaks islater, and the C_(max) for the second peak is higher. Thus, the skilledperson can adjust the relative C_(max) and AUC for each of the two peaksby adjusting the relative amounts of coated and uncoated drug-resinparticles in the composition.

Example 13 Ethanol Study

A. In Vivo Study

The effects of ethanol were also tested. In vivo studies were carriedout using drug samples similar to that from Example 6 administered topigs as described in Example 11. The drug formulations were administeredto pigs as described in Example 11, except that alcohol (240 ml of 20%ethanol) was also administered to the pigs contemporaneously. Capsulesof ADDERALL XR were administered under the same conditions as controls.

Results of the pig study are depicted in FIGS. 10A and 10B. Outlierswere excluded. FIGS. 3A and 3B show the plasma concentrations of drugreleased from the resin formulas similar to that in Example 6 comparedto ADDERALL XR (i.e., the reference formulation) and IR mixedamphetamines in the presence and absence of alcohol. The figures show(1) an increased exposure of amphetamines in the presence of alcohol;and (2) in the present of ethanol, formulations of the invention have asignificantly reduced exposure level of amphetamines as compared toADDERALL XR as demonstrated by comparison between the curves shown.

Often drugs products exhibit dose dumping in the presence of ethanol.This is one of the reason that the FDA asks for ethanol interactionstudies on controlled release formulations. If a drug product showeddose dumping, all of the drug that is to be administered over time wouldbecome immediately available and adverse events could be seen. Incontrast, the graph clearly shows that the integrity of the controlledrelease mechanism remains intact and two peaks can be distinguished. Thefirst peak being the immediate release portion and the second peak beingthe still intact delayed release portion. The increased exposure,approximately 3 times the area under the curve (AUC), for both peaks isdue to another physiological effect in the presence of ethanol such asimpairment of the liver metabolism by the ethanol and thus lower firstpass metabolism of the drug in the liver or other mechanism resulting ingreater than expected blood levels for a given dose.

B. In Vitro Study

In vitro dissolution studies using amphetamine compositions in thepresence or absence of ethanol were also carried out. Drug compositionsto be tested were introduced into USP dissolution Apparatus 2 asdescribed above, except that the media started with alcoholic 0.1N HCland samples were taken at different time points. FIG. 11 shows therelease profiles of the ADDERALL XR reference formulation with 0%, 20%,and 40% ethanol. These results demonstrate that the addition of 20% or40% ethanol substantially increases the amount of drug released in thereference formulation, i.e., there is a substantial increase in drugreleased through dose dumping in the presence of ethanol. This dosedumping may exacerbate the exposure of the subject to amphetamines whichincreases in vivo approximately 3 times in the presence of ethanol.

FIG. 12 shows the release profiles of the drug sample similar to thatfrom Example 6 with 0%, 20%, and 40% ethanol. These results demonstratethat the addition 20% ethanol does not substantially increase the amountof drug released. Moreover, the addition of 40% ethanol increases theamount of drug released but to a lesser extent than in the referenceformulation. As such, the ethanol study's results show that, in thepresence of ethanol, the formulations of the invention have a reducedexposure level of amphetamines as compared to the reference formulation.This prevents or substantially reduces the likelihood of dose dumpingwhen the formulations of the invention and ethanol are ingested by asubject.

Example 14 pH Study

A pH study was also conducted on the compositions administered to thepigs in Example 13. The dissolution and pH protocols are the same asdescribed in Example 10. The results of the pH study on three differentlots of the delayed release particles from Example 6 are depicted inFIG. 13.

Example 15 Human Pharmacokinetic Study Using ODT PharmaceuticalCompositions

This example describes a single-dose, open-label, randomized,three-period, three-treatment crossover study comparing the rate ofabsorption and oral bioavailability of two controlled release ODTpreparations of mixed amphetamine polistirex (equivalent to 30 mg mixedamphetamines) to an equivalent 30 mg oral dose of the commerciallyavailable reference product, ADDERALL XR, (Shire US Inc.) following anovernight fast of at least 10 hours. Subjects were randomly assigned toa treatment sequence and received three, separate single-doseadministrations of study medication, one treatment per period, accordingto the randomization schedule. Dosing days were separated by a washoutperiod of at least 7 days.

Subjects received each of the treatments listed below during the threetreatment periods:

Treatment A: Test Formulation #1 (mixed amphetamine resins)controlled-release ODT. Test Formulation #1 is substantially similar toFormula C in Example 6. Dose=1×mixed amphetamine polistirex ODTequivalent to 30 mg mixed amphetamine salts.

Treatment B: Test Formulation #2 (mixed amphetamine resins)controlled-release ODT. Test Formulation #2 is substantially similar toFormula C in Example 6. Dose=1×mixed amphetamine polistirex ODTequivalent to 30 mg mixed amphetamine salts

Treatment C: Reference Product ADDERALL XR Shire US, Inc. Dose=1×30 mgcapsule

Clinical Procedures Summary

During each study period, 4 mL blood samples were obtained prior to eachdosing and following each dose at selected times through 60 hourspost-dose. A total of 60 pharmacokinetic blood samples were collectedfrom each subject, 20 samples in each study period. In addition, bloodwas drawn and urine was collected for clinical laboratory testing atscreening and study exit.

In each study period, subjects were admitted to the study unit in theevening prior to the scheduled dose. Subjects were confined to theresearch center during each study period until completion of the 36-hourblood collection and other study procedures. Subjects returned to thestudy unit for outpatient pharmacokinetic blood samples at 48 and 60hours. Thirty-three (33) of the 36 subjects enrolled completed thestudy.

Procedures for Collecting Samples for Pharmacokinetic Analysis

Blood samples (1×4 mL) were collected in vacutainer tubes containingK₂-EDTA as a preservative at pre-dose (0) and at 1.0, 2.0, 3.0, 4.0,5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 9.0, 10.0, 12.0, 16.0, 24.0, 36.0,48.0, and 60.0 hours after dosing.

Bioanalytical Summary

Plasma samples were analyzed for d-amphetamine and l-amphetamine by athird party laboratory using a validated LC MS MS procedure. The methodwas validated for a range of 0.500 to 80.0 ng/mL for d-amphetamine and0.200 to 32.0 ng/mL for l-amphetamine, based on the analysis of 0.150 mLof human EDTA plasma.

Pharmacokinetic Analysis

Concentration time data were analyzed by noncompartmental methods inWinNonlin. Concentration time data that were below the limit ofquantification (BLQ) were treated as zero in the data summarization anddescriptive statistics. In the pharmacokinetic analysis, BLQconcentrations were treated as zero from time-zero up to the time atwhich the first quantifiable concentration was observed; embedded and/orterminal BLQ concentrations were treated as “missing”. Full precisionconcentration data (not rounded to three significant figures) and actualsample times were used for all pharmacokinetic and statistical analyses.

The following pharmacokinetic parameters were calculated: peakconcentration in plasma (C_(max)), time to peak concentration (T_(max)),elimination rate constant (λz), terminal half-life (T½), area under theconcentration-time curve from time-zero to the time of the lastquantifiable concentration (AUC_(last)), and area under the plasmaconcentration time curve from time-zero extrapolated to infinity(AUC_(inf)). Secondary pharmacokinetic endpoints included partial AUCs.The following partial AUCs were calculated using the linear trapezoidalmethod: AUC₀₋₄, AUC₄₋₁₂, and AUC₀₋₂₄.

Analysis of variance (ANOVA) and the Schuirmann's two one sided t testprocedures at the 5% significance level were applied to thelog-transformed pharmacokinetic exposure parameters, C_(max),AUC_(last), and AUC_(inf). The 90% confidence interval for the ratio ofthe geometric means (Test/Reference) was calculated. Bioequivalence wasdeclared if the lower and upper confidence intervals of thelog-transformed parameters were within 80% to 125%. Comparisons ofpartial AUC₀₋₄, AUC₄₋₁₂, and AUC₀₋₂₄ across treatments were performed assupportive evidence of equivalence.

Results

Data from 33 subjects who completed the study were included in thepharmacokinetic and statistical analyses. Mean concentration-time dataare shown in FIGS. 14 and 15. Results of the pharmacokinetic andstatistical analyses are shown below in Tables 8 through 11.

The results show that the d- and l-amphetamine enantiomers of TestFormulations #1 and #2 were bioequivalent to the Reference Product. Inparticular, nearly all of the partial AUCs (AUC₄₋₁₂ and AUC₀₋₂₄) of thed- and l-amphetamine enantiomers of Test Formulations #1 and #2 werebioequivalent to the Reference Product.

FIGS. 14A and 14B show the mean d-amphetamine concentration-timeprofiles after administration of Test Formulation #1 (Treatment A), TestFormulation #2 (Treatment B), and Reference Product (Treatment C).

FIGS. 15A and 15B show the mean l-amphetamine concentration-timeprofiles after administration of test formulation #1 (Treatment A), testformulation #2 (Treatment B), and reference product (Treatment C).

TABLE 8 Statistical analysis of the log-transformed systemic exposureparameters of d-amphetamine comparing Test Formulation #1 (Treatment A)to the Reference Product (Treatment C). Dependent Geometric Mean^(a)Ratio (%)^(b) 90% CI^(c) ANOVA Variable Test Ref (Test/Ref) Lower UpperPower CV % ln(C_(max)) 44.5370 45.9975 96.82 94.62 99.08 1.0000 5.61ln(AUC₀₋₄) 85.9326 100.9418 85.13 78.30 92.56 0.9965 20.54 ln(AUC₄₋₁₂)290.8805 294.3597 98.82 96.85 100.82 1.0000 4.89 ln(AUC₀₋₂₄₎ 613.2608631.8461 97.06 94.84 99.32 1.0000 5.61 ln(AUC_(last)) 825.7531 843.470097.90 94.99 100.90 1.0000 7.34 ln(AUC_(inf)) 848.3149 866.4947 97.9094.73 101.18 1.0000 7.88 ^(a)Geometric Mean for the Test Formulation #1(Test) and Reference Product (Ref) based on Least Squares Mean oflog-transformed parameter values ^(b)Ratio (%) = Geometric Mean(Test)/Geometric Mean (Ref) ^(c)90% Confidence Interval Note: T_(1/2)and parameters based on extrapolation could not be calculated for allsubjects; statistical analysis is based on n = 33 for C_(max), AUC₀₋₄,AUC₄₋₁₂, AUC₀₋₂₄, AUC_(last), and n = 32 for AUC_(inf)

TABLE 9 Statistical analysis of the log-transformed systemic exposureparameters of d-amphetamine comparing Test Formulation #2 (Treatment B)to the Reference Product (Treatment C). Dependent Geometric Mean^(a)Ratio (%)^(b) 90% CI^(c) ANOVA Variable Test Ref (Test/Ref) Lower UpperPower CV % ln(C_(max)) 45.2664 45.9975 98.41 96.17 100.70 1.0000 5.61ln(AUC₀₋₄) 80.8609 100.9418 80.11 73.68 87.09 0.9965 20.54 ln(AUC₄₋₁₂)295.5819 294.3597 100.42 98.42 102.45 1.0000 4.89 ln(AUC₀₋₂₄₎ 616.5054631.8461 97.57 95.35 99.85 1.0000 5.61 ln(AUC_(last)) 830.7075 843.470098.49 95.56 101.50 1.0000 7.34 ln(AUC_(inf)) 851.1774 866.4947 98.2395.05 101.52 1.0000 7.88 ^(a)Geometric Mean for the Test Formulation #2(Test) and Reference Product (Ref) based on Least Squares Mean oflog-transformed parameter values ^(b)Ratio (%) = Geometric Mean(Test)/Geometric Mean (Ref) ^(c)90% Confidence Interval Note: T_(1/2)and parameters based on extrapolation could not be calculated for allsubjects; statistical analysis is based on n = 33 for C_(max), AUC₀₋₄,AUC₄₋₁₂, AUC₀₋₂₄, AUC_(last), and n = 32 for AUC_(inf)

TABLE 10 Statistical analysis of the log-transformed systemic exposureparameters of l-amphetamine comparing Test Formulation #1 (Treatment A)to the Reference Product (Treatment C). Dependent Geometric Mean^(a)Ratio (%)^(b) 90% CI^(c) ANOVA Variable Test Ref (Test/Ref) Lower UpperPower CV % ln(C_(max)) 14.2494 14.1857 100.45 98.07 102.89 1.0000 5.85ln(AUC₀₋₄) 26.3537 30.0286 87.76 80.53 95.64 0.9951 21.14 ln(AUC₄₋₁₂)95.1124 93.0132 102.26 100.09 104.47 1.0000 5.20 ln(AUC₀₋₂₄₎ 204.9113203.7331 100.58 98.07 103.15 1.0000 6.14 ln(AUC_(last)) 295.5590290.6272 101.70 98.33 105.18 1.0000 8.21 ln(AUC_(inf)) 312.0976 307.0441101.65 97.80 105.64 1.0000 9.24 ^(a)Geometric Mean for the TestFormulation #1 (Test) and Reference Product (Ref) based on Least SquaresMean of log-transformed parameter values ^(b)Ratio (%) = Geometric Mean(Test)/Geometric Mean (Ref) ^(c)90% Confidence Interval Note: T_(1/2)and parameters based on extrapolation could not be calculated for allsubjects; statistical analysis is based on n = 33 for C_(max), AUC₀₋₄,AUC₄₋₁₂, AUC₀₋₂₄, AUC_(last), and n = 32 for AUC_(inf)

TABLE 11 Statistical analysis of the log-transformed systemic exposureparameters of 1-amphetamine comparing Test Formulation # 2 (Treatment B)to the Reference Product (Treatment C). Dependent Geometric Mean^(a)Ratio (%)^(b) 90% CI^(c) ANOVA Variable Test Ref (Test/Ref) Lower UpperPower CV % ln(C_(max)) 14.6051 14.1857 102.96 100.51 105.46 1.0000 5.85ln(AUC₀₋₄) 24.9270 30.0286 83.01 76.17 90.46 0.9951 21.14 ln(AUC₄₋₁₂)96.8135 93.0132 104.09 101.88 106.34 1.0000 5.20 ln(AUC₀₋₂₄) 206.6684203.7331 101.44 98.91 104.03 1.0000 6.14 ln(AUC_(last)) 297.5544290.6272 102.38 98.99 105.89 1.0000 8.21 ln(AUC_(inf)) 313.3883 307.0441102.07 98.21 106.07 1.0000 9.24 ^(a)Geometric Mean for the TestFormulation # 2 (Test) and Reference Product (Ref) based on LeastSquares Mean of log-transformed parameter values ^(b)Ratio (%) =Geometric Mean (Test)/Geometric Mean (Ref) ^(c)90% Confidence IntervalNote: T_(1/2) and parameters based on extrapolation could not becalculated for all subjects; statistical analysis is based on n = 33 forC_(max), AUC₀₋₄, AUC₄₋₁₂, AUC₀₋₂₄, AUC_(last), and n = 32 for AUC_(inf)

Example 16 Human Pharmacokinetic Study Comparing ODT to SuspensionFormulations

This example compared the rate of absorption and oral bioavailability ofa controlled release ODT preparation of mixed amphetamine polistirex(equivalent to 30 mg mixed amphetamine salts) and a controlled releaseliquid suspension of mixed amphetamine polistirex (equivalent to 30 mgmixed amphetamine salts) to an equivalent 30 mg oral dose of thecommercially available reference product, ADDERALL XR (Shire US Inc.)following an overnight fast of at least 10 hours. Subjects were randomlyassigned to a treatment sequence and received three separate single-doseadministrations of study medication, one treatment per period, accordingto the randomization schedule as described in the previous Example.Dosing days were separated by a washout period of at least 7 days.

Subjects received each of the treatments listed below during the threetreatment periods:

Treatment A: Test Formulation #3 (mixed amphetamine resins)controlled-release ODT. Dose=1×mixed amphetamine polistirex ODTequivalent to 30 mg mixed amphetamine salts.

Treatment B: Test Formulation #4 (mixed amphetamine resins)controlled-release suspension. Dose=1×mixed amphetamine polistirexsuspension equivalent to 30 mg mixed amphetamine salts.

Treatment C: Reference Product ADDERALL XR, Shire US, Inc. Dose=1×30 mgcapsule.

TABLE 12 Test Formulation #3 (ODT amphetamine with 45% IR and 55% DR)

IR Resin - 34.08% base assay & DR Resin - 7.28% base assay: These valueswill be variable

TABLE 13 Test Formulation #4 (Suspension amphetamine with 45% IR and 55%DR)

IR Resin - 34.08% base assay % DR Resin - 7.28% base assay:

Administration, data collection and analysis were carried out asdescribed in the previous Example. Data from subjects who completed thestudy were included in the pharmacokinetic and statistical analyses.Mean concentration-time data are shown in FIGS. 16-19. Results of thepharmacokinetic and statistical analyses are shown below in Tables 14through 17.

TABLE 14 Statistical Analysis of Human Bioequivalence Studies: ODT Data(D- Isomer) Mean Ratio (%) 90% CI Dependent Variable Test Ref (Test/Ref)Lower Upper ln(C_(max)) 44.5 46.0 96.7 94.6 99.1 ln(AUC₀₋₄) 85.9 100.985.1 78.3 92.6 ln(AUC₀₋₅) 126.3 46.0 (?) 87.7 82.1 93.7 ln(AUC₄₋₁₂)290.9 294.4 98.8 96.9 100.8 ln(AUC₅₋₁₂) 250.5 251.6 99.5 97.3 101.8ln(AUC₀₋₂₄) 613.3 631.8 97.1 94.8 99.3 ln(AUC_(last)) 825.8 843.5 97.995.0 100.9 ln(AUC_(inf)) 848.3 866.5 97.9 94.7 101.2 T_(max) 5.26 4.53

TABLE 15 Statistical Analysis of Human Bioequivalence Studies: ODT Data(L- Isomer) Mean Ratio (%) 90% CI Dependent Variable Test Ref (Test/Ref)Lower Upper ln(C_(max)) 14.2 14.2 100.5 98.1 102.9 ln(AUC₀₋₄) 26.4 30.087.8 80.5 95.6 ln(AUC₀₋₅) 39.2 43.2 90.7 84.6 97.1 ln(AUC₄₋₁₂) 95.1 93.0102.3 100.1 104.5 ln(AUC₅₋₁₂) 82.3 79.9 103.0 100.5 105.5 ln(AUC₀₋₂₄)204.9 203.7 100.6 98.1 103.2 ln(AUC_(last)) 295.6 290.6 101.7 98.3 105.2ln(AUC_(inf)) 312.1 307.0 101.7 97.8 105.6 T_(max) 5.70 4.59

TABLE 16 Statistical Analysis of Human Bioequivalence Studies:Suspension Data (D-Isomer) Mean Ratio (%) 90% CI Dependent Variable TestRef (Test/Ref) Lower Upper ln(C_(max)) 46.3 49.1 94.2 91.4 97.0ln(AUC₀₋₄) 104.7 107.4 97.5 88.7 107.0 ln(AUC₀₋₅) 148.6 152.4 97.5 90.7104.9 ln(AUC₄₋₁₂) 300.4 313.8 95.7 92.7 98.9 ln(AUC₅₋₁₂) 256.9 269.195.5 92.1 98.9 ln(AUC₀₋₂₄) 651.8 680.2 95.8 92.6 99.2 ln(AUC_(last))861.2 904.5 95.2 91.0 99.6 ln(AUC_(inf)) 892.8 935.4 95.4 91.0 100.1T_(max) 4.61 4.96

TABLE 17 Statistical Analysis of Human Bioequivalence Studies:Suspension Data (L-Isomer) Mean Ratio (%) 90% CI Dependent Variable TestRef (Test/Ref) Lower Upper ln(C_(max)) 14.6 14.8 98.9 96.3 101.6ln(AUC₀₋₄) 31.8 31.6 100.8 91.6 110.8 ln(AUC₀₋₅) 45.7 45.2 101.1 93.8108.9 ln(AUC₄₋₁₂) 96.8 97.1 99.7 96.4 103.2 ln(AUC₅₋₁₂) 83.2 83.6 99.595.9 103.2 ln(AUC₀₋₂₄) 215.2 215.5 99.9 96.3 103.6 ln(AUC_(last)) 304.8306.8 99.3 94.6 104.4 ln(AUC_(inf)) 325.3 327.0 99.5 94.0 105.2 T_(max)5.09 5.27

Example 17 Orally Disintegrating Tablet with 25% IR and 75% ER/DR

An orally disintegrating tablet was formulated with 25% ofmethylphenidate from immediate release resin complex and 75% of themethylphenidate from an extended release (ER)/delayed release (DR) resincomplex. In the ER/DR coating, ethylcellulose overlays EUDRAGIT. Theformula is presented below.

TABLE 18 ODT methylphenidate Formulation A with 25% IR and 75% ER/DR.

IR Resin - 36.98% base assay & ER/DR Resin - 13.11% base assay: Thesevalues are variable

TABLE 19 ODT methylphenidate Formulation B with 25% IR and 75% ER/DR.

IR Resin - 36.98% base assay & ER/DR Resin - 12.77% base assay: Thesevalues are variable.

These formulas are exactly the same except for the level of actualethylcellulose coating (as determined by assay). Formula “A” has 18.6%ethylcellulose coating and “B” has 20.7%. These are the calculatedcoating levels of ethylcellulose prior to the EUDRAGIT coating.

Dissolution Method

Dissolution testing is carried out using an Apparatus 2 with cannulasand cannula filters (Quality Lab Accessories, Porus Micron full flowfilters 20 micron); paddle speed—100 rpm; kettle size-1000 mL;temperature—37.0±0.5° C.; filter—25 mm 0.45 um PTFE; syringe—B-D10 mLLuer-Lok.

Dissolution Media:

The medium for the dissolution assay is 900 mL of 0.1N HCl for the firsthour; after 2 hour time point ˜100 mL of potassium phosphate/sodiumhydroxide solution is added to bring to pH ˜6.8.

The sample is weighed and is placed into the corresponding kettle, andthe dissolution timing started.

Sampling pull times are 30 minutes, 2 hours, 4 hours and 8 hours. Foreach sample pull time and each kettle, 10 mL of sample are pulled into aB-D 10 mL Luer-Lok syringe and returned to the kettles before the samplepull to flush out the cannula from the prior pulls. 4 ml are then pulledfor filtration, discarding the first 2 ml to waste and the remainingsample into an HPLC vial. Non-media replacement and volume changes fromthe two media changes are calculated.

Dissolution Profile:

The amount of drug in the filtrate at each time point is determined byHPLC, and the percentage released from Formulae A and B, respectively,are shown below and in FIG. 26.

Formula A Profile Profile Hours (% Release) 0.5 31% 2 39% 4 79% 8 87% 2487%

Formula B Profile Profile Hours (% Release) 0.5 32% 2 41% 4 80% 8 90% 2490%

Example 18 Human Pharmacokinetic Study Using ODT PharmaceuticalCompositions

This example describes a single-dose, open-label, randomized,three-period, three-treatment crossover study comparing the rate ofabsorption and oral bioavailability of two controlled release ODTpreparations of methylphenidate polistirex (equivalent to 60 mgmethylphenidate) to an equivalent 60 mg oral dose of the commerciallyavailable reference product, METADATE CD, (UCB, Inc.) following anovernight fast of at least 10 hours. Subjects were randomly assigned toa treatment sequence and received three, separate single-doseadministrations of study medication, one treatment per period, accordingto the randomization schedule. Dosing days were separated by a washoutperiod of at least 7 days.

Subjects received each of the treatments listed below during the threetreatment periods:

Treatment A: Test Formulation #1 (methylphenidate resins)controlled-release ODT. Test Formulation #1 is substantially similar tothe formulation A described in Example 17. Dose=2×methylphenidatepolistirex ODT containing 26.1 mg methylphenidate base, equivalent to 60mg methylphenidate HCl.

Treatment B: Test Formulation #2 (methylphenidate resins)controlled-release ODT. Test Formulation #2 is substantially similar tothe formulation B described in Example 17. Dose=2×methylphenidatepolistirex ODT containing 26.1 mg methylphenidate base, equivalent to 60mg methylphenidate HCl.

Treatment C: Reference Product METADATE CD UCB, Inc. Dose=1×60 mgcapsule

Clinical Procedures Summary

During each study period, 6 mL blood samples were obtained prior to eachdosing and following each dose at selected times through 36 hourspost-dose. A total of 63 pharmacokinetic blood samples were collectedfrom each subject, 21 samples in each study period. In addition, bloodwas drawn and urine was collected for clinical laboratory testing atscreening and study exit.

In each study period, subjects were admitted to the study unit in theevening prior to the scheduled dose. Subjects were confined to theresearch center during each study period until completion of the 24-hourblood collection and other study procedures. Subjects returned to thestudy unit for outpatient pharmacokinetic blood samples at 36 hours.Thirty-eight (38) of the 42 subjects enrolled completed the study.

Procedures for Collecting Samples for Pharmacokinetic Analysis

Blood samples (1×6 mL) were collected in vacutainer tubes containingK₂-EDTA as a preservative at pre-dose (0) and at 0.5, 1.0, 1.5, 2.0,2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 8.0, 10.0, 12.0, 18.0,24.0, and 36.0 hours after dosing.

Bioanalytical Summary

Plasma samples were analyzed for d-methylphenidate and 1-methylphenidateby a third party laboratory using a validated LC-MS-MS procedure. Themethod was validated for a range of 0.250 to 50.0 ng/mL ford-methylphenidate and 0.0100 to 2.00 ng/mL for 1-methylphenidate, basedon the analysis of 0.100 mL of human EDTA plasma.

Pharmacokinetic Analysis

Concentration time data were analyzed by noncompartmental methods inWinNonlin. Concentration time data that were below the limit ofquantification (BLQ) were treated as zero in the data summarization anddescriptive statistics. In the pharmacokinetic analysis, BLQconcentrations were treated as zero from time-zero up to the time atwhich the first quantifiable concentration was observed; embedded and/orterminal BLQ concentrations were treated as “missing”. Full precisionconcentration data (not rounded to three significant figures) and actualsample times were used for all pharmacokinetic and statistical analyses.

The following pharmacokinetic parameters were calculated ford-methylphenidate, 1-methylphenidate, and total methylphenidate (d+l):peak concentration in plasma (C_(max)), time to peak concentration(T_(max)), elimination rate constant (λz), terminal half-life (T½), areaunder the concentration-time curve from time-zero to the time of thelast quantifiable concentration (AUC_(last)), and area under the plasmaconcentration time curve from time-zero extrapolated to infinity(AUC_(inf)). Secondary pharmacokinetic endpoints included partial AUCs.The following partial AUCs were calculated using the linear trapezoidalmethod: AUC₀₋₃, AUC0-_(tmax) (AUC₀₋₅), AUC_(tmax-24) (AUC₅₋₂₄), AUC₀₋₂₄,and AUC_(tmax-tlast).

Test Formulations #1 and #2 were compared to the reference product.Analysis of variance (ANOVA) and the Schuirmann's two one sided t testprocedures at the 5% significance level were applied to thelog-transformed pharmacokinetic exposure parameters, C_(max),AUC_(last), and AUC_(inf) d-methylphenidate, l-methylphenidate, andtotal methylphenidate (d+l). The 90% confidence interval for the ratioof the geometric means (Test/Reference) was calculated. Bioequivalencewas declared if the lower and upper confidence intervals of thelog-transformed parameters were within 80% to 125%. mComparisons ofpartial AUCs, AUC₀₋₃, AUC0-_(tmax) (AUC₀₋₅), AUC_(tmax-24) (AUC₅₋₂₄),AUC₀₋₂₄, and AUC_(tmax-tlast) across treatments were performed assupportive evidence of equivalence.

Results

Data from 38 subjects who completed the study were included in thepharmacokinetic and statistical analyses.

FIGS. 20A and 20B show the mean linear and log d-methylphenidateconcentration-time profiles after administration of Test Formulation #1(Treatment A), Test Formulation #2 (Treatment B), and Reference Product(Treatment C).

FIGS. 21A and 21B show the mean linear and log 1-methylphenidateconcentration-time profiles after administration of Test Formulation #1(Treatment A), Test Formulation #2 (Treatment B), and Reference Product(Treatment C).

FIGS. 22A and 22B show the mean linear and log total methylphenidate(d+l) concentration-time profiles after administration of TestFormulation #1 (Treatment A), Test Formulation #2 (Treatment B), andReference Product (Treatment C).

TABLE 20 Statistical Analysis of the Log-Transformed Systemic ExposureParameters of d-Methylphenidate Comparing Test Formulation 1 (TreatmentA) to the Reference Product (Treatment C) Dependent Geometric Mean^(a)Ratio (%)^(b) 90% CI^(c) ANOVA Variable Test Ref (Test/Ref) Lower UpperPower CV % ln(C_(max)) 20.1714 16.3095 123.68 117.21 130.50 1.0000 14.10ln(AUC₀₋₃) 20.5344 23.7682 86.39 79.10 94.36 0.9935 23.36ln(AUC_(0-tmax)) ^(d) 50.1624 50.0850 100.15 93.53 107.25 0.9998 18.03ln(AUC_(tmax-24)) ^(d) 103.8409 95.3024 108.96 104.11 114.04 1.000011.94 ln(AUC₀₋₂₄₎ 156.7217 146.3987 107.05 103.73 110.48 1.0000 8.25ln(AUC_(tmax-tlast)) ^(d) 104.3909 100.4459 103.93 98.76 109.37 1.000013.39 ln(AUC_(last)) 157.4500 151.7064 103.79 100.26 107.44 1.0000 9.05ln(AUC_(inf)) 161.1557 157.9722 102.02 98.78 105.35 1.0000 8.43^(a)Geometric Mean for the Test Formulation 1 (Test) and ReferenceProduct (Ref) based on Least Squares Mean of log-transformed parametervalues ^(b)Ratio (%) = Geometric Mean (Test)/Geometric Mean (Ref)^(c)90% Confidence Interval ^(d)The median T_(max) of the ReferenceProduct (5.00 hr) was used

TABLE 21 Statistical Analysis of the Log-Transformed Systemic ExposureParameters of d-Methylphenidate Comparing Test Formulation 2 (TreatmentB) to the Reference Product (Treatment C). Dependent Geometric Mean^(a)Ratio (%)^(b) 90% CI^(c) ANOVA Variable Test Ref (Test/Ref) Lower UpperPower CV % ln(C_(max)) 20.4113 16.3095 125.15 118.62 132.04 1.0000 14.10ln(AUC₀₋₃) 21.7843 23.7682 91.65 83.92 100.10 0.9936 23.36ln(AUC_(0-tmax)) ^(d) 51.9061 50.0850 103.64 96.79 110.97 0.9998 18.03ln(AUC_(tmax-24)) ^(d) 105.8856 95.3024 111.10 106.16 116.27 1.000011.94 ln(AUC₀₋₂₄₎ 160.7525 146.3987 109.80 106.40 113.31 1.0000 8.25ln(AUC_(tmax-tlast)) ^(d) 106.3546 100.4459 105.88 100.62 111.42 1.000013.39 ln(AUC_(last)) 161.3617 151.7064 106.36 102.75 110.10 1.0000 9.05ln(AUC_(inf)) 165.4229 157.9722 104.72 101.40 108.14 1.0000 8.43^(a)Geometric Mean for the Test Formulation 2 (Test) and ReferenceProduct (Ref) based on Least Squares Mean of log-transformed parametervalues ^(b)Ratio(%) = Geometric Mean (Test)/Geometric Mean (Ref) ^(c)90%Confidence Interval ^(d)The median T_(max) of the Reference Product(5.00 hr) was used

TABLE 22 Statistical Analysis of the Log-Transformed Systemic ExposureParameters of/-Methylphenidate Comparing Test Formulation 1 (TreatmentA) to the Reference Product (Treatment C). Dependent Geometric Mean^(a)Ratio (%)^(b) 90% CI^(c) ANOVA Variable Test Ref (Test/Ref) Lower UpperPower CV % ln(C_(max)) 0.4471 0.2224 201.01 167.90 240.64 0.6550 49.75ln(AUC₀₋₃) 0.6292 0.2691 233.82 198.86 274.92 0.7346 44.29ln(AUC_(0-tmax)) ^(d) 1.0739 0.5281 203.35 175.47 235.66 0.8024 40.01ln(AUC_(tmax-24)) ^(d) 0.9649 0.7668 125.84 108.56 145.87 0.8013 40.08ln(AUC₀₋₂₄₎ 2.1909 1.3404 163.45 143.93 185.62 0.8936 34.18ln(AUC_(tmax-tlast)) ^(d) 0.8821 0.7435 118.64 101.75 138.33 0.773641.81 ln(AUC_(last)) 2.1125 1.3231 159.66 140.14 181.90 0.8801 35.09ln(AUC_(inf)) 2.2098 1.5598 141.68 122.06 164.44 0.7952 40.46^(a)Geometric Mean for the Test Formulation 1 (Test) and ReferenceProduct (Ref) based on Least Squares Mean of log-transformed parametervalues ^(b)Ratio(%) = Geometric Mean (Test)/Geometric Mean (Ref) ^(c)90%Confidence Interval ^(d)The median T_(max) of the Reference Product(5.00 hr) was used

TABLE 23 Statistical Analysis of the Log-Transformed Systemic ExposureParameters of/-Methyphenidate Comparing Test Formulation 2 (Treatment B)to the Reference Product (Treatment C) Dependent Geometric Mean^(a)Ratio (%)^(b) 90% CI^(c) ANOVA Variable Test Ref (Test/Ref) Lower UpperPower CV % ln(C_(max)) 0.5092 0.2224 228.93 191.26 274.02 0.6557 49.75ln(AUC₀₋₃) 0.6798 0.2691 252.63 214.89 296.99 0.7354 44.29ln(AUC_(0-tmax)) ^(d) 1.1261 0.5281 213.23 184.02 247.07 0.8031 40.01ln(AUC_(tmax-24)) ^(d) 1.1095 0.7668 144.70 124.85 167.70 0.8021 40.08ln(AUC₀₋₂₄₎ 2.4426 1.3404 182.23 160.49 206.92 0.8942 34.18ln(AUC_(tmax-tlast)) ^(d) 1.0239 0.7435 137.71 118.13 160.55 0.774441.81 ln(AUC_(last)) 2.3641 1.3231 178.68 156.86 203.54 0.8807 35.09ln(AUC_(inf)) 2.4774 1.5598 158.83 136.87 184.32 0.7959 40.46^(a)Geometric Mean for the Test Formulation 2 (Test) and ReferenceProduct (Ref) based on Least Squares Mean of log-transformed parametervalues ^(b)Ratio(%) = Geometric Mean (Test)/Geometric Mean (Ref) ^(c)90%Confidence Interval ^(d)The median T_(max) of the Reference Product(5.00 hr) was used

TABLE 24 Statistical Analysis of the Log-Transformed Systemic ExposureParameters of Total Methylphenidate (d + l) Comparing Test Formulation 1(Treatment A) to the Reference Product (Treatment C) Dependent GeometricMean^(a) Ratio (%)^(b) 90% CI^(c) ANOVA Variable Test Ref (Test/Ref)Lower Upper Power CV % ln(C_(max)) 20.6080 16.5477 124.54 117.98 131.461.0000 14.21 ln(AUC₀₋₃) 21.2961 24.1188 88.30 80.92 96.35 0.9943 23.10ln(AUC_(0-tmax)) ^(d) 51.4307 50.7312 101.38 94.67 108.56 0.9998 18.02ln(AUC_(tmax-24)) ^(d) 105.0763 96.2603 109.16 104.30 114.24 1.000011.94 ln(AUC₀₋₂₄₎ 159.2597 148.0008 107.61 104.29 111.03 1.0000 8.20ln(AUC_(tmax-tlast)) ^(d) 105.6235 102.0912 103.46 98.33 108.86 1.000013.35 ln(AUC_(last)) 159.9855 153.9687 103.91 100.39 107.55 1.0000 9.03ln(AUC_(inf)) 163.6833 159.5401 102.60 99.37 105.93 1.0000 8.36^(a)Geometric Mean for the Test Formulation 1 (Test) and ReferenceProduct (Ref) based on Least Squares Mean of log-transformed parametervalues ^(b)Ratio(%) = Geometric Mean (Test)/Geometric Mean (Ref) ^(c)90%Confidence Interval ^(d)The median T_(max) of the Reference Product(5.00 hr) was used

TABLE 25 Statistical Analysis of the Log-Transformed Systemic ExposureParameters of Total Methylphenidate (d + l) Comparing Test Formulation 2(Treatment B) to the Reference Product (Treatment C). DependentGeometric Mean^(a) Ratio (%)^(b) 90% CI^(c) ANOVA Variable Test Ref(Test/Ref) Lower Upper Test CV % ln(C_(max)) 20.8467 16.5477 125.98119.35 132.97 1.0000 14.21 ln(AUC₀₋₃) 22.5591 24.1188 93.53 85.73 102.050.9944 23.10 ln(AUC_(0-tmax)) ^(d) 53.1774 50.7312 104.82 97.90 112.240.9998 18.02 ln(AUC_(tmax-24)) ^(d) 107.4905 96.2603 111.67 106.70116.86 1.0000 11.94 ln(AUC₀₋₂₄₎ 163.6952 148.0008 110.60 107.20 114.121.0000 8.20 ln(AUC_(tmax-tlast)) ^(d) 108.1238 102.0912 105.91 100.66111.43 1.0000 13.35 ln(AUC_(last)) 164.4747 153.9687 106.82 103.21110.57 1.0000 9.03 ln(AUC_(inf)) 168.3659 159.5401 105.53 102.22 108.951.0000 8.36 ^(a)Geometric Mean for the Test Formulation 2 (Test) andReference Product (Ref) based on Least Squares Mean of log-transformedparameter values ^(b)Ratio(%) = Geometric Mean (Test)/Geometric Mean(Ref) ^(c)90% Confidence Interval ^(d)The median T_(max) of theReference Product (5.00 hr) was used

Conclusions

Based on C_(max), the peak exposure to d-methylphenidate is higher afteradministration of Test Formulations 1 and 2 relative to that afterMETADATE CD and the 90% confidence intervals about the ratios forC_(max) (Test Formulation 1/Reference and Test Formulation 2/Reference)are not within the 80% to 125% range necessary to establish traditionalbioequivalence. However, based on AUC_(last) and AUC_(inf), the overallsystemic exposure to d-methylphenidate after administration of TestFormulations 1 and 2 is comparable to that after METADATE CD and the 90%confidence intervals about the ratios for AUC_(last) and AUC_(inf) arewithin the 80% to 125% range, indicating no significant difference inbioavailability. Except for AUC₀₋₃ after Test Formulation 1 (ratio:86.39%; 90% confidence interval: 79.10%-94.36%), the 90% confidenceintervals about the Test/Reference ratios for all partial AUCs arewithin the 80% to 125% range, indicating comparable early systemicexposure through T_(max) (5.00 hr) and 24 hours after Test Formulations1 and 2 relative to METADATE CD.

Based on C_(max), AUC_(last), and AUC_(inf), peak and overall systemicexposure to l-methylphenidate is higher after administration of TestFormulations 1 and 2 relative to that after METADATE CD and the 90%confidence intervals about the Test/Reference ratios (Test Formulation1/Reference and Test Formulation 2/Reference) are not within the 80% to125% range necessary to establish traditional bioequivalence. Similarly,based on partial AUCs, early systemic exposure to l-methylphenidate ishigher after administration of Test Formulations 1 and 2 relative tothat after METADATE CD and the 90% confidence intervals about theTest/Reference ratios for all partial AUCs are not within the 80% to125% range.

Based on AUC_(last) and AUC_(inf), the overall systemic exposure tototal methylphenidate (d+l) after administration of Test Formulations 1and 2 is comparable to that after METADATE CD and the 90% confidenceintervals about the ratios for AUC_(last) and AUC_(inf) are within the80% to 125% range, indicating no significant difference inbioavailability. In addition, the 90% confidence intervals about theTest/Reference ratios for all partial AUCs are within the 80% to 125%range, indicating comparable early systemic exposure through 3 hours,T_(max) (5.00 hr), and 24 hours after Test Formulations 1 and 2 relativeto METADATE CD.

Example 19 Ethanol Study

In vitro dissolution studies using methylphenidate compositions in thepresence or absence of ethanol were also carried out. One 60 mg capsuleof METADATE CD, and separately, two (30 mg) tablets of a formulationsimilar to Example 17, were introduced into USP dissolution Apparatus 2.The dissolution media started with alcoholic 0.1N HCl with variousamounts of ethanol (0%, 5%, 10%, 20%, and 40%). Appropriate amounts ofpH change buffer were added to the media at 2 hours (after the samplewas introduced) to make the pH of the media to 6.8. Samples were takenat different time points. The results are shown in FIGS. 25A (METADATECD), 25B (test formulation) and 25C (METADATE CD and test formulation).

FIG. 25A shows that the addition of 40% ethanol substantially increasesthe amount of drug released in the reference formulation, i.e., there isa substantial increase in drug released through dose dumping in thepresence of ethanol.

FIG. 25B shows that the addition 40% ethanol increases the amount ofdrug released but to a lesser extent than in the reference formulation.As such, the ethanol study's results show that, in the presence ofethanol, the formulations of the invention have a reduced exposure levelof methylphenidate as compared to the reference formulation. Thisprevents or substantially reduces the likelihood of dose dumping whenthe formulations of the invention and ethanol are ingested by a subject.

Example 20 Food-Effect Study of an Extended Release Methylphenidate ODTFormulation in Healthy Subjects

This example describes a single-dose, open-label, randomized, two-periodcrossover study that assessed the effect of food on the rate ofabsorption and oral bioavailability of a single dose (two ODTs) of amethylphenidate extended release ODT (equivalent to 60 mgmethylphenidate HCl), under fed and fasted conditions.

Subjects in both treatment conditions fasted overnight for at least 10hours. Subjects in the fed condition were dosed 5 minutes aftercompleting consumption of a Food and Drug Administration (FDA) standardhigh-calorie, high-fat breakfast meal. Consumption of the FDA standardhigh-calorie, high-fat breakfast began 30 minutes prior to dosing.Subjects in the fasted condition continued to fast up until the timethat they were dosed. Each drug administration was separated by awashout period of 7 days.

Subjects were administered a single 2 ODT dose of each of the treatmentsin a randomized, sequenced fashion. Immediately prior to dose, eachsubject was given 60 mL of room temperature water in a cup andinstructed to swish the water around in the mouth and to spit it out inorder to wet the mouth.

Treatment A (Fasted): Test Formulation #102 (shown below) was orallyadministered following a 10-hour overnight fast. Dose=2×methylphenidatepolistirex ODT containing 26.1 mg methylphenidate base Formulation #102,equivalent to 60 mg of methylphenidate HCl.

Treatment B (Fed): Test Formulation #102 (shown below) was orallyadministered following a 10-hour overnight fast and consumption of anFDA standard high-fat, high-calorie breakfast beginning 30 minutes priorto dose. Dose=2×methylphenidate polistirex ODT, each containing 26.1 mgmethylphenidate base Formulation #102; this dose is equivalent to 60 mgof methylphenidate HCl.

The subjects fasted for 4 hours thereafter. Standard meals were providedat approximately 4 and 10 hours after drug administration and atappropriate times thereafter.

Except for the 60 mL mouth rinse given immediately prior to each dose(and which the subjects spit out), no water was allowed for 1 hour priorthrough 1 hour after dose. Each subject was required to drinkapproximately 360 mL of fluid with each snack or meal administeredduring confinement after dosing on Day 1. Each subject was required todrink 120 mL of water at approximately 1, 2, and 3 hours after doseadministration. Subjects were provided approximately 700 mL of waterthat was required to be consumed between lunch and snack administrationsduring confinement on Day 1. After snack administration on Day 1, waterwas allowed ad lib.

TABLE 26 ODT methylphenidate Formulation #102 with 25% IR and 75% ER/DR

IR Resin - 36.97% base assay & ER/DR Resin - 12.88% base assay

Data collection and analysis were carried out as similarly as describedabove. Twenty-three (23) of the 24 subjects enrolled completed thestudy. Data from 23 subjects were included in the pharmacokinetic andstatistical analyses Mean concentration-time data are shown in FIGS.27-29. Results of the pharmacokinetic and statistical analysis are shownbelow in Tables 27 through 29.

Results:

FIGS. 27A and 27B show the mean methylphenidate (d+l) concentration-timeprofiles after administration of Formulation #102-Fasted (Treatment A)and Formulation #102-Fed (Treatment B).

FIGS. 28A and 28B mean d-methylphenidate concentration-time profilesafter administration of Formulation #102-Fasted (Treatment A) andFormulation #102-Fed (Treatment B).

FIGS. 29A and 29B mean l-methylphenidate concentration-time profilesafter administration of Formulation #102-Fasted (Treatment A) andFormulation #102-Fed (Treatment B).

TABLE 27 Statistical Analysis of the Log-Transformed Systemic ExposureParameters of Methylphenidate (d + l) Dependent Geometric Mean^(a) Ratio(%)^(b) 90% CI^(c) ANOVA Variable Test Ref (Test/Ref) Lower Upper PowerCV % ln(C_(max)) 22.4817 25.9799 86.53 80.52 93.00 0.9992 14.25ln(AUC_(last)) 229.2966 205.8759 111.38 106.74 116.21 1.0000 8.38ln(AUC_(inf)) 237.5598 211.0504 112.56 108.18 117.11 1.0000 7.82^(a)Geometric Mean for Formulation #102-Fed (Test) and Formulation#102-Fasted (Ref) based on Least Squares Mean of log-transformedparameter values ^(b)Ratio(%) = Geometric Mean (Test)/Geometric Mean(Ref) ^(c)90% Confidence Interval

TABLE 28 Statistical Analysis of the Log-Transformed Systemic ExposureParameters of d-Methylphenidate Dependent Geometric Mean^(a) Ratio(%)^(b) 90% CI^(c) ANOVA Variable Test Ref (Test/Ref) Lower Upper PowerCV % ln(C_(max)) 22.1811 25.5705 86.74 80.74 93.20 0.9992 14.20ln(AUC_(last)) 226.7299 203.5182 111.41 106.79 116.22 1.0000 8.34ln(AUC_(inf)) 234.9939 208.7056 112.60 108.24 117.13 1.0000 7.78^(a)Geometric Mean for Formulation #102-Fed (Test) and Formulation#102-Fasted (Ref) based on Least Squares Mean of log-transformedparameter values ^(b)Ratio(%) = Geometric Mean (Test)/Geometric Mean(Ref) ^(c)90% Confidence Interval

TABLE 29 Statistical Analysis of the Log-Transformed Systemic ExposureParameters of/-Methylphenidate Dependent Geometric Mean^(a) Ratio(%)^(b) 90% CI^(c) Variable Test Ref (Test/Ref) Lower Upper Power ANOVACV % ln(C_(max)) 0.3806 0.4171 91.25 74.52 111.73 0.5695 41.51ln(AUC_(last)) 2.1957 1.9338 113.54 99.76 129.23 0.8869 25.90ln(AUC_(inf)) 2.3594 2.0529 114.93 100.74 131.12 0.8768 26.40^(a)Geometric Mean for Formulation #102-Fed (Test) and Formulation#102-Fasted (Ref) based on Least Squares Mean of log-transformedparameter values ^(b)Ratio(%) = Geometric Mean (Test)/Geometric Mean(Ref) ^(c)90% Confidence Interval

Conclusions

There were no unusual or unexpected adverse events (AEs) related to thestudy medication. In general, the AE profile was consistent with themechanism of action for this drug.

The 90% confidence intervals for comparing the log-transformed exposureparameters ln(C_(max)), ln(AUC_(last)), and ln(AUC_(inf)) were withinthe accepted 80% to 125% limits for the a priori designated endpoint,methylphenidate (d+l).

Therefore, the presence of food did not significantly altermethylphenidate (d+l) exposure following the administration ofmethlyphenidate-polistirex formulated as ODT (equivalent to 60 mgmethylphenidate HCl) under fasting and fed conditions.

Example 21 The Effect of Food on the Pharmacokinetics of a ControlledRelease Amphetamine ODT in Healthy Subjects

This example describes a single-dose, open-label, randomized,two-period, two-treatment crossover study that assessed the effect offood on the rate of absorption and oral bioavailability of a controlledrelease ODT preparations of mixed amphetamine polistirex (equivalent to30 mg mixed amphetamines), under fed and fasted conditions.

The protocol was the same as described in Example 20, except subjectsreceived treatment listed below during the two treatment periods:

Treatment A (Fed Conditions): Test Formulation #1002A (mixed amphetamineresins) controlled-release ODT (shown below). Dose=1×mixed amphetaminepolistirex ODT equivalent to 30 mg mixed amphetamine salts.

Treatment B (Fasted Conditions): Test Formulation #1002A (mixedamphetamine resins) controlled-release ODT (shown below). Dose=1×mixedamphetamine polistirex ODT equivalent to 30 mg mixed amphetamine salts.

TABLE 30 ODT amphetamine formulation with 45% IR and 55% DR

IR Resin - 34.08% base assay & DR Resin - 7.28% base assay

Data collection and analysis were carried out similarly as describedabove. All 16 subjects enrolled completed the study. Data from the 16subjects were included in the pharmacokinetic and statistical analyses.Mean concentration-time data are shown in FIGS. 30 and 31. Results ofthe pharmacokinetic and statistical analysis are shown below in Tables31 and 32.

Results

TABLE 31 Statistical Analysis of the Log-Transformed Systemic ExposureParameters of d-amphetamine Comparing Test Formulation-Fed (Treatment A)to Test Formulation-Fasted (Treatment B) Dependent Geometric Mean^(a)Ratio (%)^(b) 90% CI^(c) Variable Fed Fasted (Fed/Fasted) Lower UpperPower ANOVA CV % ln(C_(max)) 40.8357 47.6112 85.77 81.34 90.44 1.00008.54 ln(AUC_(last)) 886.6801 962.1617 92.16 88.40 96.07 1.0000 6.68ln(AUC_(inf)) 941.2440 1018.5933 92.41 88.11 96.91 1.0000 7.35^(a)Geometric Mean for the Test Formulation-Fed and TestFormulation-Fasted based on Least Squares Mean of log-transformedparameter values ^(b)Ratio(%) = Geometric Mean (Fed)/Geometric Mean(Fasted) ^(c)90% Confidence Interval Note: T_(1/2) and parameters basedon extrapolation could not be calculated for all subjects; statisticalanalysis is based on n = 16 C_(max), AUC_(last) and n = 15 for AUC_(inf)

TABLE 32 Statistical Analysis of the Log-Transformed Systemic ExposureParameters of/-amphetamine Comparing Test Formulation-Fed (Treatment A)to Test Formulation-Fasted (Treatment B) Ratio (%)^(b) DependentGeometric Mean^(a) (Fed/ 90% CI^(c) ANOVA Variable Fed Fasted Fasted)Lower Upper Power CV % ln(C_(max)) 12.8378 14.8236 86.60 82.37 91.061.0000 8.07 ln(AUC_(last)) 312.5311 342.9993 91.12 86.84 95.61 1.00007.74 ln(AUC_(inf)) 346.2042 378.5080 91.47 86.33 96.91 0.9999 8.94^(a)Geometric Mean for the Test Formulation-Fed and TestFormulation-Fasted based on Least Squares Mean of log-transformedparameter values ^(b)Ratio(%) = Geometric Mean (Fed)/Geometric Mean(Fasted) ^(c)90% Confidence Interval Note: T_(1/2) and parameters basedon extrapolation could not be calculated for all subjects; statisticalanalysis is based on n = 16 for C_(max), AUC_(last) and n = 15 forAUC_(inf)

Conclusions

There were no unusual or unexpected adverse events related to the studymedication. Study exit clinical laboratory, ECG, and physicalexamination evaluations were completed with no clinically significantfindings. The 90% confidence intervals for comparing the maximumexposure, based on ln(C_(max)), are within 80% to 125% for both d- andl-amphetamine. The 90% confidence intervals for comparing total systemicexposure, based on ln(AUC_(last)) and ln(AUC_(inf)), are within 80% to125% for both d- and l-amphetamine. On the other hand, T_(max) valueswere statistically different for the two treatments.

These data confirm that the extended-release characteristics of ODTcontaining amphetamine polistirex were maintained in the presence of ahigh-fat meal, and that a high-fat meal does not have a significanteffect on the rate of absorption or oral bioavailability of mixedamphetamine resins in controlled-release ODT.

Example 22 The Effect of Alcohol on the Pharmacokinetics of a ControlledRelease Amphetamine ODT in Healthy Subjects

This example describes a single-dose, open-label, randomized,four-period, four-treatment, four-sequence crossover study that assessedthe effect of varying concentrations of alcohol on the rate ofabsorption and oral bioavailability of a controlled release ODTpreparation of mixed amphetamine polistirex (equivalent to 30 mg mixedamphetamines), in healthy adults.

Subjects fasted overnight for at least 10 hours, but were administeredintravenous (IV) fluids continuously from approximately 10 hours predoseto approximately 2 hours predose. The subjects received doseadministrations of a controlled-release ODT preparation of amphetaminesfollowed by varying concentrations of alcohol. Subjects were assigned toone of two cohorts (Group 1 or Group 2), randomly assigned to atreatment sequence, and received four, separate single-doseadministrations of study medication, one treatment per period, accordingto the randomization schedule. Dosing days were separated by a washoutperiod of at least 14 days. Subjects were divided into two groups of 16.

Subjects received the treatments listed below during the four treatmentperiods:

Treatment A: Test Formulation #1002A (described in Example 21)controlled-release ODT followed by 240 mL of deionized water (0%ethanol).

Treatment B: Test Formulation #1002A (described in Example 21)controlled-release ODT followed by 240 mL of 4% ethanol solution.

Treatment C: Test Formulation #1002A (described in Example 21)controlled-release ODT followed by 240 mL of 20% ethanol solution

Treatment D: Test Formulation #1002A (described in Example 21)controlled-release ODT followed by 240 mL of 40% ethanol solution.

Subjects were given a single oral dose of the formulation followed byvarying amounts of alcohol at a pre-specified time in each period, aftera 10 hour overnight fast that was preceded by a standard meal. Thesubjects fasted for 4 hours thereafter. Water was allowed ad lib duringthe study except for 1 hour prior through 1 hour post-dose. Standardmeals were provided at approximately 4 and 10 hours after drugadministration and at appropriate times thereafter.

The water and/or alcohol solution was administered followingconfirmation that the ODT formulation had completely disintegrated. Thedeionized water and/or alcohol solution was consumed within 30 minutes.

Data collection and analysis were carried out as similarly as describedabove. Twenty seven (27) of the 32 subjects enrolled completed thestudy. Data from 32 subjects who completed at least one study periodwere included in the pharmacokinetic and statistical analyses. Meanconcentration-time data are showing in FIGS. 32 and 33. Results of thepharmacokinetic and statistical analysis are shown below in Tables 33through 38.

Results

FIGS. 32A and 32B show mean d-amphetamine concentration-time profilesafter administration of controlled Release ODT with Deionized Water (0%Ethanol Solution) (Treatment A), 4% ethanol (Treatment B), 20% ethanol(Treatment C) and 40% ethanol (Treatment D) on linear (upper panel) andsemi-logarithmic (lower panel) scales.

FIGS. 33A and 33B show mean l-amphetamine concentration-time profilesafter administration of controlled Release ODT with Deionized Water (0%Ethanol Solution) (Treatment A), 4% ethanol (Treatment B), 20% ethanol(Treatment C) and 40% ethanol (Treatment D) on linear (upper panel) andsemi-logarithmic (lower panel) scales.

TABLE 33 Statistical Analysis of the Log-Transformed Systemic ExposureParameters of d-amphetamine Comparing Formula #1002A + 4% Ethanol(Treatment B) to Formula #1002A + Deionized Water (0% Ethanol Solution)(Treatment A) Dependent Geometric Mean^(a) Ratio (%)^(b) 90% CI^(c)ANOVA Variable Test Ref (Test/Ref) Lower Upper Power CV % ln(C_(max))42.6047 41.6151 102.38 98.11 106.83 1.0000 9.88 ln(AUC_(last)) 880.9005854.9740 103.03 97.48 108.90 1.0000 12.88 ln(AUC_(inf))^(GRP1) 1000.2608931.5954 107.37 102.69 112.27 1.0000 6.96 ln(AUC_(inf))^(GRP2) 909.5489865.2939 105.11 100.49 109.95 1.0000 7.39 ^(a)Geometric Mean for Formula#1002A + 4% Ethanol (Test) Formula #1002A + Deionized Water (0% EthanolSolution) (Ref) based on Least Squares Mean of log-transformed parametervalues ^(b)Ratio(%) = Geometric Mean (Test)/Geometric Mean (Ref) ^(c)90%Confidence Interval ^(GRP1/GRP2) = Group 1/Group 2

TABLE 34 Statistical Analysis of the Log-Transformed Systemic ExposureParameters of d-amphetamine Comparing Formula #1002A + 20% Ethanol(Treatment C) to Formula #1002A + Deionized Water (0% Ethanol Solution)(Treatment A) Dependent Geometric Mean^(a) Ratio (%)^(b) 90% CI^(c)ANOVA Variable Test Ref (Test/Ref) Lower Upper Power CV % ln(C_(max))40.0621 41.6151 96.27 92.21 100.51 1.0000 9.88 ln(AUC_(last)) 841.7095854.9740 98.45 93.08 104.13 1.0000 12.88 ln(AUC_(inf))^(GRP1) 895.8201931.5954 96.16 91.85 100.67 1.0000 6.96 ln(AUC_(inf))^(GRP2) 916.3051865.2939 105.90 101.24 110.77 1.0000 7.39 ^(a)Geometric Mean for Formula#1002A + 4% Ethanol (Test) Formula #1002A + Deionized Water (0% EthanolSolution) (Ref) based on Least Squares Mean of log-transformed parametervalues ^(b)Ratio(%) = Geometric Mean (Test)/Geometric Mean (Ref) ^(c)90%Confidence Interval ^(GRP1/GRP2) = Group 1/Group 2

TABLE 35 Statistical Analysis of the Log-Transformed Systemic ExposureParameters of d-amphetamine Comparing Formula #1002A + 40% Ethanol(Treatment D) to Formula #1002A + Deionized Water (0% Ethanol Solution)(Treatment A) Dependent Geometric Mean^(a) Ratio (%)^(b) 90% CI^(c)ANOVA Variable Test Ref (Test/Ref) Lower Upper Power CV % ln(C_(max))39.5057 41.6151 94.93 90.88 99.17 1.0000 9.88 ln(AUC_(last)) 848.9149854.9740 99.29 93.81 105.10 1.0000 12.88 ln(AUC_(inf))^(GRP1) 908.1250931.5954 97.48 93.18 101.98 1.0000 6.96 ln(AUC_(inf))^(GRP2) 868.8805865.2939 100.41 95.91 105.13 1.0000 7.39 ^(a)Geometric Mean for Formula#1002A + 4% Ethanol (Test) Formula #1002A + Deionized Water (0% EthanolSolution) (Ref) based on Least Squares Mean of log-transformed parametervalues ^(b)Ratio(%) = Geometric Mean (Test)/Geometric Mean (Ref) ^(c)90%Confidence Interval ^(GRP1/GRP2) = Group 1/Group 2

TABLE 36 Statistical Analysis of the Log-Transformed Systemic ExposureParameters of l-amphetamine Comparing Formula #1002A + 4% Ethanol(Treatment B) to Formula #1002A + Deionized Water (0% Ethanol Solution)(Treatment A) Dependent Geometric Mean^(a) Ratio (%)^(b) 90% CI^(c)ANOVA Variable Test Ref (Test/Ref) Lower Upper Power CV % ln(C_(max))13.6773 13.3098 102.76 98.64 107.05 1.0000 9.50 ln(AUC_(last)) 316.6826307.3284 103.04 96.77 109.73 1.0000 14.63 ln(AUC_(inf)) ^(GRP1) 379.7166345.8712 109.79 103.92 115.98 1.0000 8.56 ln(AUC_(inf)) ^(GRP2) 342.6777325.5756 105.25 100.16 110.60 1.000 8.15 ^(a)Geometric Mean for Formula#1002A + 4% Ethanol (Test) and Formula #1002A + Deionized Water (0%Ethanol Solution) (Ref) based on Least Squares Mean of log-transformedparameter values ^(b)Ratio(%) = Geometric Mean (Test)/Geometric Mean(Ref) ^(c)90% Confidence Interval ^(GRP1/GRP2) = Group 1/Group 2

TABLE 37 Statistical Analysis of the Log-Transformed Systemic ExposureParameters of l-amphetamine Comparing Formula #1002A + 20% Ethanol(Treatment C) to Formula #1002A + Deionized Water (0% Ethanol Solution)(Treatment A) Dependent Geometric Mean^(a) Ratio (%)^(b) 90% CI^(c)ANOVA Variable Test Ref (Test/Ref) Lower Upper Power CV % ln(C_(max))12.9647 13.3098 97.41 93.45 101.53 1.0000 9.50 ln(AUC_(last)) 301.3609307.3284 98.06 92.01 104.50 1.0000 14.63 ln(AUC_(inf)) ^(GRP1) 333.1404345.8712 96.32 91.03 101.91 1.000 8.56 ln(AUC_(inf)) ^(GRP2) 346.3956325.5756 106.39 101.25 111.80 1.0000 8.15 ^(a)Geometric Mean for Formula#1002A + 20% Ethanol (Test) and Formula #1002A + Deionized Water (0%Ethanol Solution) (Ref) based on Least Squares Mean of log-transformedparameter values ^(b)Ratio(%) = Geometric Mean (Test)/Geometric Mean(Ref) ^(c)90% Confidence Interval ^(GRP1/GRP2) = Group 1/Group 2

TABLE 38 Statistical Analysis of the Log-Transformed Systemic ExposureParameters of l-amphetamine Comparing Formula #1002A + 40% Ethanol(Treatment D) to Formula #1002A + Deionized Water (0% Ethanol Solution)(Treatment A) Dependent Geometric Mean^(a) Ratio (%)^(b) 90% CI^(c)ANOVA Variable Test Ref (Test/Ref) Lower Upper Power CV % ln(C_(max))12.6112 13.3098 94.75 90.86 98.81 1.0000 9.50 ln(AUC_(last)) 306.0284307.3284 99.58 93.36 106.21 1.0000 14.63 ln(AUC_(inf)) ^(GRP1) 337.9262345.8712 97.70 92.43 103.27 1.0000 8.56 ln(AUC_(inf)) ^(GRP2) 328.1746325.5756 100.80 95.83 106.03 1.0000 8.15 ^(a)Geometric Mean for Formula#1002A + 40% Ethanol (Test) and Formula #1002A + Deionized Water (0%Ethanol Solution) (Ref) based on Least Squares Mean of log-transformedparameter values ^(b)Ratio(%) = Geometric Mean (Test)/Geometric Mean(Ref) ^(c)90% Confidence Interval ^(GRP1/GRP2) = Group 1/Group 2

Conclusions:

The 90% confidence intervals for comparing the maximum exposure tod-amphetamine and l-amphetamine, based on ln(C_(max)), are within theaccepted 80% to 125% limits across all comparisons

The 90% confidence intervals for comparing total systemic exposure tod-amphetamine and l-amphetamine, based on ln(AUC_(last)) andln(AUC_(inf)), are within the accepted 80% to 125% limits across allcomparisons.

Therefore, varying concentrations of alcohol (4%-40% ethanol solution)did not significantly alter the rate and extent of absorption of Formula#1002A amphetamine polistirex (equivalent to 30 mg mixed amphetaminesalts), in healthy subjects. The results of this study indicate that thecontrolled-release properties of formulations according to thisinvention are maintained in the presence of alcohol.

Example 23 Human Pharmacokinetic Study of a Controlled ReleaseAmphetamine ODT Under Fasted Conditions in Children with ADHD

This example describes a single-dose, open-label, single-period,one-treatment study to determine the pharmacokinetic profile of acontrolled release ODT preparation of mixed amphetamine polistirex(equivalent to 30 mg mixed amphetamines), in children (6-12 years old).Subjects were children diagnosed with ADHD, and 28 enrolled childrenwere divided into three cohorts (6 of 6-7 years, 11 of 8-9 years, and 11of 10-12 years).

Following a 10-hour overnight fast, subjects received 1 dose of TestFormulation #1002A (described in Example 21). This dose was administeredwithout water (other than a small mouth rinse (which was not ingested)prior to drug administration) and allowed to disintegrate on the tongue.After dosing, no food was allowed until 4 hours post-dose. No water wasto be consumed for 1 hour prior through 1 hour post-dose.

Subjects remained in the research center until completion of the 12-hourblood sampling for the study period and returned for outpatient visitsat approximately 24 (Visit 3), 36 (Visit 4), and 48 hours (Visit 5)post-dose in the study period. After the final plasma sample wascollected, subjects were permitted to resume taking their usual dose ofamphetamines. The final safety visit took place 2 days after dosing aspart of Visit 5 (Day 7).

During the study period, 3 mL blood samples were obtained prior todosing and following the dose at selected times through 48 hourspost-dose. Data collection and analysis were carried out as describedabove. The following PK parameters were determined:

-   -   λZ: The elimination rate constant (λZ) was calculated as the        negative of the slope of the terminal log-linear segment of the        plasma concentration-time curve; the range of data to be used        was determined by visual inspection of a semi-logarithmic plot        of concentration versus time.    -   CL/F: Oral clearance (CL/F) was calculated as:

CL/F=D/AUC_(inf),

-   -   -   where D was the administered dose.

    -   Vz/F: Volume of distribution in the terminal phase after oral        administration (Vz/F) was calculated as:

Vz/F=(CL/F)/λZ.

Results

Data from 28 enrolled subjects who completed the study were included inthe pharmacokinetic and statistical analyses. Mean concentration-timedata are showing in FIGS. 34 and 35. Results of the pharmacokinetic andstatistical analysis are shown below in Tables 39 and 40.

FIGS. 34A and 34B mean d-amphetamine Concentration-Time Profiles afterAdministration of Formula #1002A ODT for Group 1 (Ages 6-7), Group 2(Ages 8-9), and Group 3 (Ages 10-12).

FIGS. 35A and 35B show mean l-amphetamine Concentration-Time Profilesafter Administration of Formula #1002A ODT for Group 1 (Ages 6-7), Group2 (Ages 8-9), and Group 3 (Ages 10-12).

TABLE 39 Statistical Analysis of Weight-Normalized Clearance and Volumeof Distribution of d-amphetamine. Supplied as Formula #1002A TargetConfidence 95% Confidence Interval Range Interval 60%-140% GeometricLower Upper Lower Upper Parameter n Mean Bound Bound Bound Bound AgeGroup 1 (6-7 yrs): Vz/F (L/kg)  6 10.08 8.448 11.95 6.048 14.11 CL/F(L/h/kg)  6 0.7619 0.6682 0.8648 0.4571 1.067 Age Group 2 (8-9 yrs):Vz/F (L/kg) 11 9.177 8.284 10.28 5.506 12.85 CL/F (L/h/kg) 11 0.71170.6371 0.8057 0.4270 0.9964 Age Group 3 (10-12 yrs): Vz/F (L/kg) 118.678 8.064 9.396 5.207 12.15 CL/F (L/h/kg) 11 0.6094 0.5349 0.71060.3656 0.8532 Note: Target confidence interval range was calculated bymultiplying the geometric mean by 0.6 for the 60% lower bound and 1.4for the 140% upper bound. Abbreviations: CL/F = oral clearance; CR =controlled release; h = hour; MAR = mixed amphetamine resin; ODT = oraldisintegrating tablet; Vz/F = volume of distribution in the terminalphase after oral administration; yrs = years.

TABLE 40 Statistical Analysis of Weight-Normalized Clearance and Volumeof Distribution of l-amphetamine Supplied as Formula #1002A TargetConfidence 95% Confidence Interval Range Interval 60%-140% GeometricLower Upper Lower Upper Parameter n Mean Bound Bound Bound Bound AgeGroup 1 (6-7 yrs): Vz/F (L/kg)  6 32.68 26.72 39.63 19.61 45.75 CL/F(L/h/kg)  6 2.137 1.840 2.466 1.282 2.992 Age Group 2 (8-9 yrs): Vz/F(L/kg) 11 29.63 26.46 33.65 17.78 41.48 CL/F (L/h/kg) 11 2.019 1.7782.335 1.211 2.827 Age Group 3 (10-12 yrs): Vz/F (L/kg) 11 28.35 26.2330.84 17.01 39.69 CL/F (L/h/kg) 11 1.712 1.497 2.001 1.027 2.397 Note:Target confidence interval range was calculated by multiplying thegeometric mean by 0.6 for the 60% lower bound and 1.4 for the 140% upperbound. Abbreviations: CL/F = oral clearance; CR = controlled release; h= hour; MAR = mixed amphetamine resin; ODT = oral disintegrating tablet;Vz/F = volume of distribution in the terminal phase after oraladministration; yrs = years.

Conclusions:

There were no unusual or unexpected adverse effects (AEs) related to thestudy medication. There were no deaths, SAEs, or discontinuations. Ingeneral, the nature of the TEAEs reported was consistent with themechanism of action for these study medications.

An age-related trend in mean maximum and total d-amphetamine andl-amphetamine exposure was observed; as age increased, mean amphetamineexposure decreased. Weight did not appear to be a prominent factor inthe observed downward age-related trend in amphetamine exposure.

Mean weight-normalized CL/F and Vz/F values for d-amphetamine andl-amphetamine decreased slightly with an increase in age. Mean T_(1/2)was similar across age groups. Additionally, the geometric means and 95%CIs calculated for d-amphetamine and l-amphetamine CL/F and Vz/F werewithin the target range of 60% to 140% for each age group.

Example 24 Human Pharmacokinetic Study Using Amphetamine LiquidFormulations and ADDERALL XR Under Fasted Conditions

This was a single-dose, open-label, randomized, four-period,four-treatment crossover study that compared the rate of absorption andoral bioavailability of three different amphetamine controlled-releaseliquid suspensions (equivalent to 30 mg mixed amphetamine salts/15 mL)to an equivalent 30 mg dose of ADDERALL XR capsule, in healthy subjects.

All doses were administered after an overnight fast of at least 10hours. Each dose administration was separated by a washout period of atleast 7 days.

Subjects received the treatments listed below during the four treatmentperiods:

Treatment A: Test Formulation #1005A controlled-release liquid (shownbelow). Dose=1×15 mL of suspension. This dose was administered orallywithout water.

Treatment B: Test Formulation #1005B controlled-release liquid (shownbelow). Dose=1×15 mL of suspension. This dose was administered orallywithout water.

Treatment C: Test Formulation #1005C controlled-release liquid (shownbelow). Dose=1×15 mL of suspension. This dose was administered orallywithout water.

Treatment D (Reference Product): ADDERALL XR Shire US, Inc. Dose=1×30 mgcapsule. This dose was administered orally with 60 mL (2 fl. oz.) ofwater.

TABLE 41 Test Formulation #1005A (suspension amphetamine with 45% IR and55% DR)

IR Resin - 36.05% base assay & DR Resin - 7.82% base assay

TABLE 42 Test Formulation #1005B (suspension amphetamine with 45% IR and55% DR)

IR Resin - 36.05% base assay & DR Resin - 7.82% base assay

TABLE 43 Test Formulation #1005C (suspension amphetamine with 45% IR and55% DR)

IR Resin - 36.05% base assay & DR Resin - 7.82% base assay

Data collection and analysis were carried out as similarly describedabove. 44 subjects participated in the study with 39 subjects completingall four study periods, and 42 subjects completing at least one testperiod and the reference period of the study. Data for the 42 subjectswere included in the pharmacokinetic and statistical analyses. Meanconcentration-time data are showing in FIGS. 36 and 37. Results of thepharmacokinetic and statistical analysis are shown below in Tables 44through 49.

FIGS. 36A and 36B show mean d-amphetamine Concentration-Time Profilesafter Administration of Test Formulation #1 (Treatment A), TestFormulation #2 (Treatment B), Test Formulation #3 (Treatment C), and theReference Product (Treatment D).

FIGS. 37A and 37B show mean l-amphetamine Concentration-Time Profilesafter Administration of Test Formulation #1 (Treatment A), TestFormulation #2 (Treatment B), Test Formulation #3 (Treatment C), and theReference Product (Treatment D).

TABLE 44 Statistical Analysis of the Log-Transformed Systemic ExposureParameters of d-amphetamine Comparing Test Formulation #1 (Treatment A)to the Reference Product (Treatment D) Dependent Geometric Mean^(a)Ratio (%)^(b) 90% CI^(c) ANOVA Variable Test Ref (Test/Ref) Lower UpperPower CV % ln(C_(max)) 50.1580 49.5786 101.17 99.16 103.22 1.0000 5.43ln(AUC₀₋₅) 130.5315 153.2270 85.19 79.53 91.25 0.9997 18.76 ln(AUC₅₋₁₂)287.7548 272.5554 105.58 103.05 108.16 1.0000 6.56 ln(AUC_(5-last))823.1422 791.92221 103.94 100.64 107.35 1.0000 8.75 ln(AUC₀₋₂₄) 696.5164696.4442 100.01 98.18 101.88 1.0000 5.01 ln(AUC_(last)) 958.9738951.6525 100.77 98.40 103.19 1.0000 6.45 ln(AUC_(inf)) 1001.0534995.6153 100.55 97.95 103.21 1.0000 7.10 ^(a)Geometric Mean for TestFormulation #1 (Test) and Reference Product (Ref) based on Least SquaresMean of log-transformed parameter values ^(b)Ratio(%) = Geometric Mean(Test)/Geometric Mean (Ref) ^(c)90% Confidence Interval

TABLE 45 Statistical Analysis of the Log-Transformed Systemic ExposureParameters of d-amphetamine Comparing Test Formulation #2 (Treatment B)to the Reference Product (Treatment D) Dependent Geometric Mean^(a)Ratio (%)^(b) 90% CI^(c) ANOVA Variable Test Ref (Test/Ref) Lower UpperPower CV % ln(C_(max)) 50.0963 49.3574 101.50 99.82 103.20 1.0000 4.42ln(AUC₀₋₅) 135.9603 152.6483 89.07 84.05 94.38 1.0000 15.45 ln(AUC₅₋₁₂)286.6888 271.5835 105.56 103.52 107.64 1.0000 5.18 ln(AUC_(5-last))821.7640 789.8344 104.04 100.69 107.51 1.0000 8.71 ln(AUC₀₋₂₄) 699.0396694.7072 100.62 98.59 102.70 1.0000 5.41 ln(AUC_(last)) 960.8482949.2052 101.23 98.63 103.90 1.0000 6.91 ln(AUC_(inf)) 1003.0198993.2407 100.98 98.07 103.99 1.0000 7.79 ^(a)Geometric Mean for TestFormulation #2 (Test) and Reference Product (Ref) based on Least SquaresMean of log-transformed parameter values ^(b)Ratio(%) = Geometric Mean(Test)/Geometric Mean (Ref) ^(c)90% Confidence Interval

TABLE 46 Statistical Analysis of the Log-Transformed Systemic ExposureParameters of d-amphetamine Comparing Test Formulation #3 (Treatment C)to the Reference Product (Treatment D) Dependent Geometric Mean^(a)Ratio (%)^(b) 90% CI^(c) ANOVA Variable Test Ref (Test/Ref) Lower UpperPower CV % ln(C_(max)) 50.7295 49.3066 102.89 100.35 105.49 1.0000 6.51ln(AUC₀₋₅) 136.5321 152.7544 89.38 84.81 94.20 1.0000 13.75 ln(AUC₅₋₁₂)289.7260 271.3370 106.78 105.26 108.31 1.0000 3.72 ln(AUC_(5-last))829.3721 787.7095 105.29 102.81 107.83 1.0000 6.22 ln(AUC₀₋₂₄) 705.8156693.9269 101.71 99.85 103.61 1.0000 4.82 ln(AUC_(last)) 970.1670947.3535 102.41 100.17 104.69 1.0000 5.76 ln(AUC_(inf)) 1015.0619991.6597 102.36 99.66 105.13 1.0000 6.96 ^(a)Geometric Mean for TestFormulation #3 (Test) and Reference Product (Ref) based on Least SquaresMean of log-transformed parameter values ^(b)Ratio(%) = Geometric Mean(Test)/Geometric Mean (Ref) ^(c)90% Confidence Interval

TABLE 47 Statistical Analysis of the Log-Transformed Systemic ExposureParameters of l-amphetamine Comparing Test Formulation #1 (Treatment A)to the Reference Product (Treatment D) Dependent Geometric Mean^(a)Ratio (%)^(b) 90% CI^(c) ANOVA Variable Test Ref (Test/Ref) Lower UpperPower CV % ln(C_(max)) 15.6903 14.9321 105.08 102.81 107.40 1.0000 5.92ln(AUC₀₋₅) 39.6019 45.0296 87.95 81.98 94.35 0.9996 19.20 ln(AUC₅₋₁₂)92.7020 85.1083 108.92 106.39 111.52 1.0000 6.39 ln(AUC_(5-last))302.9169 283.7188 106.77 103.27 110.38 1.0000 9.03 ln(AUC₀₋₂₄) 230.3610222.7249 103.43 101.39 105.51 1.0000 5.40 ln(AUC_(last)) 344.2092330.7995 104.05 101.35 106.83 1.0000 7.14 ln(AUC_(inf)) 373.9861360.6700 103.69 100.39 107.10 1.0000 8.78 ^(a)Geometric Mean for TestFormulation #1 (Test) and Reference Product (Ref) based on Least SquaresMean of log-transformed parameter values ^(b)Ratio(%) = Geometric Mean(Test)/Geometric Mean (Ref) ^(c)90% Confidence Interval

TABLE 48 Statistical Analysis of the Log-Transformed Systemic ExposureParameters of l-amphetamine Comparing Test Formulation #2 (Treatment B)to the Reference Product (Treatment D) Dependent Geometric Mean^(a)Ratio (%)^(b) 90% CI^(c) ANOVA Variable Test Ref (Test/Ref) Lower UpperPower CV % ln(C_(max)) 15.6747 14.8460 105.58 103.86 107.33 1.0000 4.36ln(AUC₀₋₅) 41.2088 44.8276 91.93 86.65 97.52 1.0000 15.75 ln(AUC₅₋₁₂)92.3827 84.8244 108.91 106.73 111.14 1.0000 5.37 ln(AUC_(5-last))303.6696 283.1073 107.26 103.43 111.24 1.0000 9.66 ln(AUC₀₋₂₄) 231.4482222.2016 104.16 101.78 106.59 1.0000 6.12 ln(AUC_(last)) 345.8479330.0470 104.79 101.67 108.00 1.0000 8.02 ln(AUC_(inf)) 375.9631360.0332 104.42 100.75 108.23 1.0000 9.51 ^(a)Geometric Mean for TestFormulation #2 (Test) and Reference Product (Ref) based on Least SquaresMean of log-transformed parameter values ^(b)Ratio(%) = Geometric Mean(Test)/Geometric Mean (Ref) ^(c)90% Confidence Interval

TABLE 49 Statistical Analysis of the Log-Transformed Systemic ExposureParameters of l-amphetamine Comparing Test Formulation #3 (Treatment C)to the Reference Product (Treatment D) Dependent Geometric Mean^(a)Ratio (%)^(b) 90% CI^(c) ANOVA Variable Test Ref (Test/Ref) Lower UpperPower CV % ln(C_(max)) 16.0082 14.8077 108.11 105.08 111.23 1.0000 7.42ln(AUC₀₋₅) 41.4033 44.8626 92.29 87.52 97.32 1.0000 13.89 ln(AUC₅₋₁₂)93.3817 84.7844 110.14 108.48 111.83 1.0000 3.97 ln(AUC_(5-last))305.8158 282.5814 108.22 105.23 111.30 1.0000 7.32 ln(AUC₀₋₂₄) 233.5886222.0427 105.20 103.03 107.41 1.0000 5.42 ln(AUC_(last)) 348.6608329.6149 105.78 103.04 108.59 1.0000 6.85 ln(AUC_(inf)) 380.0816359.7935 105.64 101.93 109.48 1.0000 9.32 ^(a)Geometric Mean for TestFormulation #3 (Test) and Reference Product (Ref) based on Least SquaresMean of log-transformed parameter values ^(b)Ratio(%) = Geometric Mean(Test)/Geometric Mean (Ref) ^(c)90% Confidence Interval

Conclusions

There were no unusual or unexpected adverse events related to the studymedication. The 90% confidence interval for comparing the maximumexposure, based on ln(C_(max)), is within the accepted 80% to 125%limits for all comparisons and analytes.

The 90% confidence intervals for comparing total systemic exposure,based on ln(AUC_(last)) and ln(AUC_(inf)), are within the accepted 80%to 125% limits for all comparisons and analytes.

With the exception of the log-transformed AUC₀₋₃ Test Formulation #1005Avs. reference comparison for d-amphetamine, all log-transformed partialAUC parameters were within the accepted 80% to 125% range across alltreatment comparisons and analytes. The lower bound of the 90%confidence interval for the log-transformed AUC₀₋₅ Test Formulation#1005A vs. reference comparison was 79.53%, slightly below 80% ford-amphetamine.

Therefore, Test Formulations #1005B and #1005C (equivalent to 30 mgmixed amphetamine salts/15 mL) are bioequivalent to ADDERALL XR underfasted conditions.

Test Formulation #1005A (equivalent to 30 mg mixed amphetamine salts/15mL) is bioequivalent to ADDERALL XR under fasted conditions based onstandard bioequilvance metrics (C_(max), AUC_(last), AUC_(inf)) andadditional metrics such as AUC₅₋₁₂, AUC_(5-last), and AUC₀₋₂₄;bioequilvance criteria were not met for AUC₀₋₅ for d-amphetamine.

Example 25 Rate of Absorption and Oral Bioavailability of MixedAmphetaminers in Oral Liquid Suspension Compared to the CommerciallyAvailable Reference Product, Adderall XR

This was an open-label, single-dose, 3-treatment, 3-period, randomized,crossover study to assess the effect of food on the rate of absorptionand oral bioavailability of mixed amphetamines on ion exchange resin inoral liquid suspension. The oral liquid suspension is similar to thesuspension described in Example 24. Subjects were randomly assigned to atreatment sequence and received three separate single-doseadministrations of study medication, one treatment per period, accordingto the randomization schedule. Dosing days were separated by a washoutperiod of at least 7 days. Subjects received each of the treatmentslisted below during the three treatment periods:

Treatment A: Test Formulation 25A, an Oral Liquid suspension (equivalentto 30 mg mixed amphetamine salts/15 mL) was administered under fastedconditions; Dose=1×15 mL liquid oral suspension.

Treatment B: Test Formulation 25B, an Oral Liquid Suspension (equivalentto 30 mg mixed amphetamine salts/15 mL) was administered under fedconditions; Dose=1×15 mL liquid oral suspension.

Treatment C: Reference Product 25C, an Adderall XR® administered underfed conditions; Dose=1×30 mg capsule.

In each study period, subjects were admitted to the study unit in theevening prior to the scheduled dose. Subjects were confined to theresearch center during each study period until completion of the 36-hourblood collection and other study procedures. Subjects returned to thestudy unit for outpatient pharmacokinetic blood samples at 48 and 60hours.

Procedures for Collecting Samples for Pharmacokinetic Analysis

Blood samples (1×4 mL) were collected and analyzed for d- andl-amphetamine. Samples were analyzed as described above. The followingpharmacokinetic parameters were calculated: peak concentration in plasma(C_(max)), time to peak concentration (T_(max)), elimination rateconstant (λ_(z)), terminal half-life (T_(1/2)), area under theconcentration-time curve from time-zero to 5.00 hours (AUC₀₋₅), areaunder the concentration-time curve from 5.00 hours to the time of thelast quantifiable concentration (AUC_(5-last)), area under theconcentration-time curve from time-zero to the time of the lastquantifiable concentration (AUC_(last)), and area under the plasmaconcentration time curve from time-zero extrapolated to infinity(AUC_(inf)).

To assess the bioequivalence for Treatment B (fed) vs. Adderall XR(Treatment C, fed), an analysis of variance (ANOVA) model and the twoone-sided t-tests procedure was performed on the log-transformedpharmacokinetic parameters C_(max), AUC₀₋₅, AUC_(5-last), and AUC_(inf)for d- and l-amphetamine across treatments. Bioequivalence wasdemonstrated if the 90% confidence intervals were within the acceptedlimits of 80.00 to 125.00%.

To assess the effect of food on the rate and extent of absorption ofTreatment B (fed) vs. Treatment A (fast), an analysis of variance(ANOVA) model and the two one-sided t-tests procedure was performed onthe log-transformed pharmacokinetic parameters C_(max), AUC_(last), andAUC_(inf), for d- and l-amphetamine across treatments. No significantfood effect was demonstrated if the 90% confidence intervals were withinthe accepted limits of 80.00 to 125.00%.

Results

Data from 29 subjects were included in the pharmacokinetic andstatistical analyses. Mean concentration-time data are shown in FIGS. 38and 39. Results of the pharmacokinetic and statistical analyses areshown below in Tables 50 through 53.

Conclusions

Bioequivalence Assessment (Treatment B, (Fed) Vs. Adderall XR (TreatmentC, (Fed))

The 90% confidence interval for comparing the maximum exposure, based onln(C_(max)), is within the accepted 80% to 125% limits for d- andl-amphetamine. The 90% confidence intervals for comparing late and totalsystemic exposure, based on ln(AUC_(5-last)) and ln(AUC_(inf)), arewithin the accepted 80% to 125% limits for d- and l-amphetamine. The 90%confidence intervals for comparing early systemic exposure, based onln(AUC₀₋₅) are not within the accepted 80% to 125% limits for either d-and l-amphetamine. Therefore, a formulation of mixed amphetamine resinOral Liquid Suspension (equivalent to 30 mg mixed amphetamine salts/15mL) is not bioequivalent to the reference listed drug product (RLD)Adderall XR under fed conditions. Rather, formulating amphetamines in asuspension of drug-resin particles maintains an early onset ofamphetamine effect, even when taken with meals.

Food Effect Assessment (Treatment B, Fed) Vs. (Treatment A, Fast))

The 90% confidence interval for comparing the maximum exposure, based onln(C_(max)), is within the accepted 80% to 125% limits for d- andl-amphetamine. The 90% confidence intervals for comparing total systemicexposure, based on ln(AUC_(last)) and ln(AUC_(inf)), are within theaccepted 80% to 125% limits for d- and l-amphetamine. Therefore, nosignificant food effect was demonstrated for the formulations of OralLiquid Suspension containing mixed amphetamines on resin particles(equivalent to 30 mg mixed amphetamine salts/15 mL). Such suspensionsprovide amphetamine exposure levels that more closely resemble thefasted state, even when taken with meals.

TABLE 50 Statistical Analysis of the Log-Transformed Systemic ExposureParameters of d-Amphetamine Comparing Fed Conditions (Treatment B) tothe Reference Product under Fed Conditions (Treatment C) DependentGeometric Mean^(a) Ratio (%)^(b) 90% CI^(c) ANOVA Variable Test Ref(Test/Ref) Lower Upper Power CV % ln(C_(max)) 45.2535 41.6470 108.66103.14 114.47 1.0000 11.66 ln(AUC₀₋₅) 125.0648 72.1095 173.44 145.51206.73 0.6764 40.70 ln(AUC_(5-last)) 773.0222 757.8067 102.01 97.59106.63 1.0000 9.90 ln(AUC_(inf)) 945.7804 866.6134 109.14 104.84 113.611.0000 8.97 ^(a)Geometric Mean for Treatment B, Fed (Test) and ReferenceProduct-Fed (Ref) based on Least Squares Mean of log-transformedparameter values ^(b)Ratio(%) = Geometric Mean (Test)/Geometric Mean(Ref) ^(c)90% Confidence Interval

TABLE 51 Statistical Analysis of the Log-Transformed Systemic ExposureParameters of d-Amphetamine Comparing Fed Conditions (Treatment B) toFasted Conditions (Treatment A) Dependent Geometric Mean^(a) Ratio(%)^(b) 90% CI^(c) ANOVA Variable Test Ref (Test/Ref) Lower Upper PowerCV % ln(C_(max)) 45.3087 51.0913 88.68 85.41 92.08 1.0000 8.40ln(AUC_(last)) 909.6180 942.7716 96.48 93.20 99.89 1.0000 7.74ln(AUC_(inf)) 945.6631 977.1454 96.78 93.30 100.39 1.0000 8.19^(a)Geometric Mean for Treatment B, Fed (Test) and Treatment A Fasted(Ref) based on Least Squares Mean of log-transformed parameter values^(b)Ratio(%) = Geometric Mean (Test)/Geometric Mean (Ref) ^(c)90%Confidence Interval

TABLE 52 Statistical Analysis of the Log-Transformed Systemic ExposureParameters of l-Amphetamine Comparing Fed Conditions (Treatment B) tothe Reference Product under Fed Conditions (Treatment C) DependentGeometric Mean^(a) Ratio (%)^(b) 90% CI^(c) ANOVA Variable Test Ref(Test/Ref) Lower Upper Power CV % ln(C_(max)) 14.3840 12.5275 114.82109.16 120.78 1.0000 11.32 ln(AUC₀₋₅) 38.7444 20.9999 184.50 154.35220.53 0.6642 41.41 ln(AUC_(5-last)) 281.9542 258.7635 108.96 103.88114.29 1.0000 10.68 ln(AUC_(inf)) 349.4520 301.4583 115.92 110.57 121.531.0000 10.56 ^(a)Geometric Mean for Treatment B, Fed (Test) andReference Product-Fed (Ref) based on Least Squares Mean oflog-transformed parameter values ^(b)Ratio(%) = Geometric Mean(Test)/Geometric Mean (Ref) ^(c)90% Confidence Interval

TABLE 53 Statistical Analysis of the Log-Transformed Systemic ExposureParameters of l-Amphetamine Comparing Fed Conditions (Treatment B) toFasted Conditions (Treatment A) Dependent Geometric Mean^(a) Ratio(%)^(b) 90% CI^(c) ANOVA Variable Test Ref (Test/Ref) Lower Upper PowerCV % ln(C_(max)) 14.3990 16.0658 89.63 86.43 92.94 1.0000 8.11ln(AUC_(last)) 324.6557 338.2024 95.99 92.54 99.58 1.0000 8.19ln(AUC_(inf)) 349.3468 361.6533 96.60 92.75 100.61 1.0000 9.09^(a)Geometric Mean for Treatment B, Fed (Test) and Treatment A, Fasted(Ref) based on Least Squares Mean of log-transformed parameter values^(b)Ratio(%) = Geometric Mean (Test)/Geometric Mean (Ref) ^(c)90%Confidence Interval

All documents (e.g., patents and published patent applications)mentioned in this specification are hereby incorporated by reference intheir entirety.

1. A method for treating Attention-Deficit Disorder or Attention-DeficitHyperactivity Disorder comprising administering to a subject in needthereof an effective amount of a pharmaceutical composition comprisingan ADHD effective agent complexed with ion-exchange resin particles toform drug-resin particles, wherein said ADHD effective agent ismethylphenidate, and wherein said composition comprises a firstplurality of drug-resin particles that are uncoated and a secondplurality of drug-resin particles that are coated with a delayed releasecoating.
 2. The method of claim 1, wherein the second plurality ofdrug-resin particles comprises a triggered-release coating triggered bya pH change.
 3. The method of claim 2, wherein the triggered-releasecoating is cellulose acetate phthalate, cellulose acetate trimellitate,hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate,carboxymethylethylcellulose, co-polymerized methacrylic acid/methacrylicacid methyl esters, co-polymerized methacrylic acid/acrylic acid ethylesters, or mixtures thereof.
 4. The method of claim 2, wherein saiddrug-resin particles coated with a triggered-release coating furthercomprise a diffusion barrier coating.
 5. The method of claim 4, whereinthe diffusion barrier coating is a water insoluble, water permeablemembrane.
 6. The method of claim 5, wherein the diffusion barriercoating contains polyvinylpyrrolidone, polyvinylacetate,polyvinylalcohol or mixtures thereof.
 7. The method of claim 5, whereinthe water insoluble, water permeable membrane is ethylcellulose.
 8. Themethod of claim 4, wherein the triggered-release coating covers thediffusion barrier coating.
 9. The method of claim 7, wherein thediffusion barrier coating is ethylcellulose.
 10. The method of claim 1,wherein the resin particles are strong acidic cation exchange resins,selected from the group consisting of polistirex, polacrilex,cholestyramine, polacrilin or mixtures thereof.
 11. The method of claim1, wherein the composition comprises 20%-30% of the first plurality ofdrug-resin particles and 70-80% of the second plurality of drug-resinparticles.
 12. The method of claim 10, wherein the composition comprisesabout 25% of the first plurality of drug-resin particles and about 75%of the second plurality of drug-resin particles.
 13. The method of claim1, wherein the composition is a liquid suspension, chewable composition,or an orally disintegrating tablet composition.
 14. The method of claim1, wherein the amount of drug delivered to said subject is between about2 mg/24 hours to about 60 mg/24 hours.
 15. The method of claim 1,wherein the effective amount is 0.5 mg/kg/day to 1.5 mg/kg/day.
 16. Themethod of claim 1, wherein said pharmaceutical composition is sufficientto maintain an effective level of ADHD effective agent in the patientover the course of at least 8 hours without further administration ofADHD effective agent.
 17. The method of claim 1, wherein 30-33% of theADHD effective agent is released within the first 30 minutes after thedrug-resin particles are introduced into an in vitro dissolution assay,34-42% of the agent is released within 2 hours, 40-80% of the agent isreleased within 4 hours, and 80-100% of the agent is released within 24hours, wherein the conditions of the dissolution assay are an initialdissolution medium of 0.1 N HCL, and after 2 hours, the medium isadjusted to a pH of about 6.8; and the dissolution assay is performedusing a USP Apparatus
 2. 18. The method of claim 1, wherein thecomposition has an in vivo serum profile that is statistically similarto at least one profile selected from FIGS. 27-28.
 19. The method ofclaim 1, wherein the in vivo serum profile of the composition isstatistically similar to the in vivo serum profile of a composition withthe profiles of FIG.
 24. 20. A method of reducing the effects of anelevated exposure of a subject to methylphenidate, in the presence ofethanol, comprising administering the pharmaceutical composition ofclaim 1 substantially contemporaneously with ethanol, wherein thesubject is exposed to a reduced amount of methylphenidate compared toadministering a reference composition without resin particles, saidreference composition having the profiles of FIG. 23, to a subjectsubstantially contemporaneously with ethanol.
 21. The method of claim 1,wherein the amount of ADHD effective agent is equivalent to a 10 mg, 20mg, 30 mg, 40 mg, 50 mg or 60 mg reference composition without resinparticles, said reference composition having the profiles of FIG. 24.22. The method of claim 1, wherein administration of the composition toa human produces a mean plasma concentration profile in human patientswhich has one or more parameters selected from the group consisting ofAUC₀₋₃, AUC₀₋₅, AUC_(0-Tmax), AUC₅₋₁₂, AUC₅₋₂₄, AUC_(Tmax-24),AUC_(Tmax-12), AUC_(5-t), AUC_(Tmax-t), AUC₀₋₂₄, and AUC_(0-∞) ofmethylphenidate, which is substantially similar to those parameters of acomposition with the profiles of FIG.
 24. 23. The method of claim 1,wherein said composition is an orally disintegrating tablet and iseffective to provide a mean plasma concentration profile in human ADHDpatients which has an AUC₀₋₃ of 20.53 ng hr/mL −20%/+25% and a C_(max)of 20.17 ng/mL −20%/+25% for d-methylphenidate, an AUC₀₋₃ of 0.62 nghr/mL −20%/+25% and a C_(max) of 0.44 ng/mL −20%/+25% forl-methylphenidate, and/or an AUC₀₋₃ of 21.29 ng hr/mL −20%/+25% and aC_(max) of 20.60 ng/mL −20%/+25% for total methylphenidate, for a 60 mgtotal dose, or respective AUC and C_(max) values directly proportionalthereto for a total dose other than 60 mg.
 24. The method of claim 1,wherein said composition is an orally disintegrating product and iseffective to provide a mean plasma concentration profile in human ADHDpatients which has an AUC₀₋₅ of 50.16 ng hr/mL −20%/+25% and a C_(max)of 20.17 ng/mL −20%/+25% for d-methylphenidate, an AUC₀₋₅ of 1.07 nghr/mL −20%/+25% and a C_(max) of 0.44 ng/mL −20%/+25% forl-methylphenidate, and/or an AUC₀₋₅ of 51.43 ng hr/mL −20%/+25% and aC_(max) of 20.60 ng/mL −20%/+25% for total methylphenidate, for a 60 mgtotal dose, or respective AUC and C_(max) values directly proportionalthereto for a total dose other than 60 mg.
 25. The method of claim 1,wherein said composition is an orally disintegrating product and iseffective to provide a mean plasma concentration profile in human ADHDpatients which has an AUC₅₋₂₄ of 103.84 ng hr/mL −20%/+25% and a C_(max)of 20.17 ng/mL −20%/+25% for d-methylphenidate, an AUC₅₋₂₄ of 0.96 nghr/mL −20%/+25% and a C_(max) of 0.44 ng/mL −20%/+25% forl-methylphenidate, and/or an AUC₅₋₂₄ of 105.07 ng hr/mL −20%/+25% and aC_(max) of 20.60 ng/mL −20%/+25% for total methylphenidate, for a 60 mgtotal dose, or respective AUC and C_(max) values directly proportionalthereto for a total dose other than 60 mg.
 26. The method of claim 1,wherein said composition is an orally disintegrating product and iseffective to provide a mean plasma concentration profile in human ADHDpatients which has an AUC₀₋₂₄ of 156.72 ng hr/mL −20%/+25% and a C_(max)of 20.17 ng/mL −20%/+25% for d-methylphenidate, an AUC₀₋₂₄ of 2.19 nghr/mL −20%/+25% and a C_(max) of 0.44 ng/mL −20%/+25% forl-methylphenidate, and/or an AUC₀₋₂₄ of 159.25 ng hr/mL −20%/+25% and aC_(max) of 20.60 ng/mL −20%/+25% for total methylphenidate, for a 60 mgtotal dose, or respective AUC and C_(max) values directly proportionalthereto for a total dose other than 60 mg.
 27. The method of claim 1,wherein said composition, when containing about a total dose of 60 mg,will produce in a human, a mean plasma concentration versus time curve(ng/ml versus hours) having an area under the curve (AUC_(0-∞)) of about160 to about 180 for total methylphenidate.
 28. The method of claim 1,wherein one or more in vivo pharmacokinetic parameters of thecomposition selected from the group consisting of C_(max), AUC₀₋₃,AUC₀₋₅, AUC_(0-Tmax), AUC₅₋₁₂, AUC₅₋₂₄, AUC_(Tmax-24), AUC_(Tmax-12),AUC_(5-t), AUC_(Tmax-t), AUC₀₋₂₄, and AUC_(0-∞) have a 90% confidenceinterval with upper and lower bounds within a range from 90%415% of thevalue of the same parameter(s) for a bioequivalent referencecomposition.